AZINONE-SUBSTITUTED AZEPINO[b]INDOLE AND PYRIDO-PYRROLO-AZEPINE MCH-1 ANTAGONISTS, METHODS OF MAKING, AND USE THEREOF

ABSTRACT

Novel MCH-1 receptor antagonists are disclosed. These compounds are used in the treatment of various disorders, including obesity, anxiety, depression, non-alcoholic fatty liver disease, and psychiatric disorders. Methods of making these compounds are also described in the present invention.

This application claims benefit of U.S. Provisional Patent ApplicationSer. No. 61/222,437, filed Jul. 1, 2009, and U.S. Provisional PatentApplication Ser. No. 61/329,414, filed Apr. 29, 2010, which are herebyincorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to substituted azepino[b]indoles, whichare melanin-concentrating hormone (MCH-1) receptor antagonists,pharmaceutical compositions including these compounds, and methods ofpreparation and use thereof. The compounds are useful in the treatmentof obesity, anxiety, depression, non-alcoholic fatty liver disease, andpsychiatric disorders.

BACKGROUND OF THE INVENTION

Obesity and the multitude of co-morbidities associated with obesity suchas diabetes, dyslipidemia, coronary heart disease, and certain cancersare a major concern for public health. The currently availablepharmaceutical therapies for the treatment of obesity have limitedefficacy and side effects that limit their use. Thus, there is asignificant medical need for better pharmacotherapy for obesity.

Obesity has associated with it, economic and social costs. Obese people,an increasing proportion of most western societies, are regarded ashaving out of control feeding habits often associated with lowself-esteem. Moreover, obese persons are more likely to have medicalproblems associated with or exacerbated by the excess body weight.Examples of medical conditions caused, exacerbated, or triggered byexcessive weight include bone fractures, pains in the knee joints,arthritis, increased risk of hypertension, artherosclerosis, stroke, anddiabetes.

Melanin-concentrating hormone (MCH) has been identified as an orexigenicpeptide that exerts an effect on food intake and body weight regulation.MCH is a cyclic 19 amino acid neuropeptide expressed in the zona incertaand lateral hypothalamus in response to both energy restriction andleptin deficiency. MCH is known to stimulate feeding when injected intothe lateral ventricle of rats and the mRNA for MCH is upregulated in thehypothalamus of genetically obese mice (ob/ob) and in fasted control andob/ob animals. In addition, animals treated with MCH show increases inglucose, insulin and leptin levels, mimicking human metabolic syndrome(Gomori, “Chronic Infusion of MCH Causes Obesity in Mice,” Am. J.Physiol. Endocrinol. Metab., 284:E583 (2002)). Mice lacking MCH arehypophagic and lean with increased metabolic rate, whereas animalsover-expressing MCH gain excess weight on both standard and high fatdiets. MCH is thought to have effects on other nervous system functionsas well (Rocksz, “Biological Examination of Melanin ConcentratingHormone 1: Multi-tasking from the Hypothalamus,” Drug News Perspect.,19(5):273 (2006)). An orphan G-protein coupled receptor (GPCR) wasrecently identified as a receptor for MCH. Disruption of the bindingbetween MCH and the MCH receptor, i.e. MCH antagonism, may thus be usedto counteract the effects of MCH (McBriar, “Recent Advances in theDiscovery of Melanin-Concentrating Hormone Receptor Antagonists,” Curr.Opin. Drug Disc. & Dev., 9(4):496 (2006)).

The current preferred treatment for obesity as well as Type IInon-insulin dependent diabetes is diet and exercise with a view towardweight reduction and improved insulin sensitivity for diabetics. Patientcompliance, however, is usually poor. The problem is compounded by thefact that there are currently only two medications approved for thetreatment of obesity (sibutramine (MERIDIA™) and orlistat (XENICAL™).

The present invention is directed to overcoming these and otherdeficiencies in the art.

SUMMARY OF THE INVENTION

The present invention relates to a compound of formula (I):

wherein

-   R¹ is selected from the group consisting of H, —S(O)_(q)R¹⁴,    —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,    C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, and    heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆    alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, and    heteroaryl is optionally substituted with from 1 to 3 substituents    independently selected at each occurrence thereof from C₁-C₃ alkyl,    halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, and phenyl which is optionally    substituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl,    C₁-C₄ alkoxy, —CN, —OR¹⁶, or —NR¹⁶R¹⁷;-   R²-R⁵ and R⁹-R¹² are each, independently, selected from the group    consisting of H, halogen, —OR¹³, —NR¹³R¹⁴, —NR¹³C(O)R¹⁴,    —NR¹³C(O)₂R¹⁴, —NR¹⁵C(O)NR¹⁴R¹⁵, —S(O)_(q)R¹⁴, —CN, —C(O)R¹⁴,    —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆    cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and    heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆    alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl,    aryl, and heteroaryl is optionally substituted with from 1 to 3    substituents independently selected at each occurrence thereof from    C₁-C₃ alkyl, halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, and phenyl which is    optionally substituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄    haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹⁶, or —NR¹⁶R¹⁷; or R² and R³ or R⁴    and R⁵ can combine to form an oxo, thio, imine, cycloalkyl, or    heterocycle group containing from 1 to 5 heteroatoms selected from    the group consisting of oxygen, nitrogen, and sulfur;-   R⁶ is independently selected at each location from the group    consisting of H, halogen, —OR¹³, —NR¹³C(O)R¹⁴, —NR¹³C(O)₂R¹⁴,    —NR¹⁵C(O)NR¹⁴R¹⁵, —S(O)_(q)R¹⁴, —CN, —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆    alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇    cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of    C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇    cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally    substituted with from 1 to 3 substituents independently selected at    each occurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹⁶,    —NR¹⁶R¹⁷, and phenyl which is optionally substituted 1-3 times with    halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹⁶, or    —NR¹⁶R¹⁷;-   R⁷ is optionally present and, if present, is selected from the group    consisting of H, halogen, —OR¹³, —NR¹³R¹⁴, —NR¹³C(O)R¹⁴,    —NR¹³C(O)₂R¹⁴, —NR¹⁵C(O)NR¹⁴R¹⁵, —S(O)_(q)R¹⁴, —CN, —C(O)R¹⁴,    —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆    cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and    heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆    alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl,    aryl, and heteroaryl is optionally substituted with from 1 to 3    substituents independently selected at each occurrence thereof from    C₁-C₃ alkyl, halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, and phenyl which is    optionally substituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄    haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹⁶, or —NR¹⁶R¹⁷; or R² and R³ or R⁴    and R⁵ can combine to form an oxo, thio, imine, cycloalkyl, or    heterocycle group containing from 1 to 5 heteroatoms selected from    the group consisting of oxygen, nitrogen, and sulfur;-   R⁸ is selected from the group consisting of H, —S(O)_(q)R¹⁴,    —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,    C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, and    heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆    alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, and    heteroaryl is optionally substituted with from 1 to 3 substituents    independently selected at each occurrence thereof from C₁-C₃ alkyl,    halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, and phenyl which is optionally    substituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl,    C₁-C₄ alkoxy, —CN, —OR¹⁶, or —NR¹⁶R¹⁷;-   R¹³ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxyalkyl, C₃-C₆    cycloalkyl, C₄-C₇ cycloalkylalkyl, —C(O)R¹⁵, phenyl, or benzyl,    wherein phenyl or benzyl is optionally substituted 1 to 3 times with    halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄ alkoxy;-   R¹⁴ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxyalkyl, C₃-C₆    cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, or benzyl, wherein phenyl    or benzyl is optionally substituted 1 to 3 times with halogen,    cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄ alkoxy;-   R¹⁵ is C₁-C₄ alkyl, C₁-C₄ haloalkyl, or phenyl;-   R¹⁶ and R¹⁷ are each independently H, C₁-C₄ alkyl, C₁-C₄ haloalkyl,    C₁-C₄ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,    —C(O)R¹⁵, phenyl, or benzyl, wherein phenyl or benzyl is optionally    substituted from 1 to 3 times with a substituent selected    independently at each occurrence thereof from the group consisting    of halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, and C₁-C₄ alkoxy;-   R¹⁸ is selected from the group consisting of H, halogen, —OR¹³,    —NR¹³R¹⁴—NR¹³C(O)R¹⁴, —NR¹³C(O)₂R¹⁴, —NR¹⁴C(O)NR¹⁴R¹⁵, —S(O)_(q)R¹⁴,    —CN, —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆    alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl,    aryl, and heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl,    C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,    heterocyclyl, aryl, and heteroaryl is optionally substituted with    from 1 to 3 substituents independently selected at each occurrence    thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, and phenyl    which is optionally substituted 1-3 times with halogen, C₁-C₄ alkyl,    C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR⁸, or —NR⁸R⁹;-   G is —NR⁸—CR⁹R¹⁰—C¹¹R¹²—, —CR⁹R¹⁰—NR⁸—CR¹¹R¹²—, or    —CR⁹R¹⁰—C¹¹R¹²—NR⁸—, with the proviso that when G is    —CR⁹R¹⁰—NR⁸—CR¹¹R¹²—, R² and R³ are not —C(O)NR¹³R¹⁴;-   X is CR¹⁸, C(R¹⁸)₂, N, or NR¹⁸;-   Y is CR¹⁸, C, or N;-   Z is C, CH, or N;-   L is —(CH₂)_(p)—O—, —(CH₂)_(p)—, —CH═CH—, or a bond;-   A is C, CH, or N;-   B is aryl, heteroaryl, heterocyclyl, or cycloalkyl, wherein each of    the aryl, heteroaryl, heterocyclyl, or cycloalkyl is optionally    substituted with from 1 to 3 substituents selected from the group    consisting of H, alkoxy, —S-alkyl, optionally substituted C₁-C₆    alkyl, halogen, —CF₃, and —CN;-   n is 0, 1, 2, or 3;-   p is from 1 to 4;-   q is 0, 1, or 2; and-   represents an optional double bond,-   or an oxide thereof, a pharmaceutically acceptable salt thereof, a    solvate thereof, or prodrug thereof.

Additional aspects of the present invention include pharmaceuticalcompositions comprising a compound of the invention and apharmaceutically acceptable carrier and, optionally, one or moreadditional additive agent(s) as discussed below.

The present invention also relates to a method of treating a disease orcondition which is susceptible to treatment with a MCH-1 receptorantagonist. This method involves selecting a patient with a disease orcondition which is susceptible to treatment with a MCH-1 antagonist andadministering to the patient a therapeutically effective amount of acompound of formula I or a pharmaceutically acceptable salt thereof

The present invention also relates to a method of treating obesity in asubject in need of weight loss. This method involves selecting a patientin need of weight loss and administering to the patient atherapeutically effective amount of a compound of formula I or apharmaceutically acceptable salt thereof.

Yet another aspect of the present invention relates to a method oftreating obesity in a subject who has experienced weight loss. Thismethod involves selecting a patient who has experienced weight loss andadministering to the patient a therapeutically effective amount of acompound of formula I or a pharmaceutically acceptable salt thereof.

A further aspect of the present invention relates to a method oftreating anxiety. This method involves selecting a patient with anxietyand administering to the patient a therapeutically effective amount of acompound of formula I or a pharmaceutically acceptable salt thereof.

The present invention also relates to a method of treating depression.This method involves selecting a patient with depression andadministering to the patient a therapeutically effective amount of acompound of formula I or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention relates to a method of treatingnon-alcoholic fatty liver disease. This method involves selecting apatient who has non-alcoholic fatty liver disease and administering tothe patient a therapeutically effective amount of a compound of formulaI or a pharmaceutically acceptable salt thereof.

A further aspect of the present invention relates to a process forpreparation of a product compound of formula I which includes treating afirst intermediate compound of formula II:

wherein Q is a halogen, under conditions effective to form the productcompound.

It has now been found that compounds of formula I are MCH-1 receptorantagonists. This invention provides compounds that bind to the MCH-1receptor with high affinity. The compounds provided by formula I areuseful for the treatment of obesity, anxiety, depression, psychiatricdisorders, and other disorders described herein. In particular, it iscontemplated that the compounds of this invention will be effective intreating obesity, including weight loss and maintenance of weight lossin patients who have been diagnosed with obesity by the one or more ofthe following measurements: an increased body mass index, increasedwaist circumference (an indicator of intra-abdominal fat), Dual EnergyX-Ray Absorptiometry (DEXA), and trucal (android) fat mass. It isfurther contemplated that the compounds of the invention will beeffective in inducing improvements in certain factors measured in thesetests.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a compound of formula (I)

wherein

-   R¹ is selected from the group consisting of H, —S(O)_(q)R¹⁴,    —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,    C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, and    heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆    alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, and    heteroaryl is optionally substituted with from 1 to 3 substituents    independently selected at each occurrence thereof from C₁-C₃ alkyl,    halogen, —CH, —OR¹⁶, —NR¹⁶R¹⁷, and phenyl which is optionally    substituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl,    C₁-C₄ alkoxy, —CN, —OR¹⁶, or —NR¹⁶R¹⁷;-   R²-R⁵ and R⁹-R¹² are each, independently, selected from the group    consisting of H, halogen, —OR¹³, —NR¹³R¹⁴, —NR¹³C(O)R¹⁴,    —NR¹³C(O)₂R¹⁴, —NR¹⁵C(O)NR¹⁴R¹⁵, —S(O)_(q)R¹⁴, —CN, —C(O)R¹⁴,    —C(O)NR¹³R¹⁴, C₁-C₆, alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆    cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and    heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆    alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl,    aryl, and heteroaryl is optionally substituted with from 1 to 3    substituents independently selected at each occurrence thereof from    C₁-C₃ alkyl, halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, and phenyl which is    optionally substituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄    haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹⁶, or —NR¹⁶R¹⁷; or R² and R³ or R⁴    and R⁵ can combine to form an oxo, thio, imine, cycloalkyl, or    heterocycle group containing from 1 to 5 heteroatoms selected from    the group consisting of oxygen, nitrogen, and sulfur;-   R⁶ is independently selected at each location from the group    consisting of H, halogen, —OR¹³, —NR¹³C(O)R¹⁴, —NR¹³C(O)₂R¹⁴,    —NR¹⁵C(O)NR¹⁴R¹⁵, —S(O)_(q)R¹⁴, —CN, —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆    alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇    cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of    C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇    cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally    substituted with from 1 to 3 substituents independently selected at    each occurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹⁶,    —NR¹⁶R¹⁷, and phenyl which is optionally substituted 1-3 times with    halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹⁶, or    —NR¹⁶R¹⁷;-   R⁷ is optionally present and, if present, is selected from the group    consisting of H, halogen, —OR¹³, —NR¹³R¹⁴, —NR¹³C(O)R¹⁴,    —NR¹³C(O)₂R¹⁴, —NR¹⁵C(O)NR¹⁴R¹⁵, —S(O)_(q)R¹⁴, —CN, —C(O)R¹⁴,    —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂_C₆ alkynyl, C₃-C₆    cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and    heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆    alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl,    aryl, and heteroaryl is optionally substituted with from 1 to 3    substituents independently selected at each occurrence thereof from    C₁-C₃ alkyl, halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, and phenyl which is    optionally substituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄    haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹⁶, or —NR¹⁶R¹⁷; or R² and R³ or R⁴    and R⁵ can combine to form an oxo, thio, imine, cycloalkyl, or    heterocycle group containing from 1 to 5 heteroatoms selected from    the group consisting of oxygen, nitrogen, and sulfur;-   R⁸ is selected from the group consisting of H, —S(O)_(q)R¹⁴,    —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,    C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, and    heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆    alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, and    heteroaryl is optionally substituted with from 1 to 3 substituents    independently selected at each occurrence thereof from C₁-C₃ alkyl,    halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, and phenyl which is optionally    substituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl,    C₁-C₄ alkoxy, —CN, —OR¹⁶, or —NR¹⁶R¹⁷;-   R¹³ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxyalkyl, C₃-C₆    cycloalkyl, C₄-C₇ cycloalkylalkyl, —C(O)R¹⁵, phenyl, or benzyl,    wherein phenyl or benzyl is optionally substituted 1 to 3 times with    halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄ alkoxy;-   R¹⁴ is H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxyalkyl, C₃-C₆    cycloalkyl, C₄-C₇ cycloalkylalkyl, phenyl, or benzyl, wherein phenyl    or benzyl is optionally substituted 1 to 3 times with halogen,    cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄ alkoxy;-   R¹⁵ is C₁-C₄ alkyl, C₁-C₄ haloalkyl, or phenyl;-   R¹⁶ and R¹⁷ are each independently H, C₁-C₄ alkyl, C₁-C₄ haloalkyl,    C₁-C₄ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,    —C(O)R¹⁵, phenyl, or benzyl, wherein phenyl or benzyl is optionally    substituted from 1 to 3 times with a substituent selected    independently at each occurrence thereof from the group consisting    of halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, and C₁-C₄ alkoxy;-   R¹⁸ is selected from the group consisting of H, halogen, —OR¹³,    —NR¹³R¹⁴—NR¹³C(O)R¹⁴, —NR¹³C(O)₂R¹⁴, —NR¹⁴C(O)NR¹⁴R¹⁵, —S(O)_(q)R¹⁴,    —CN, —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆    alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl,    aryl, and heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl,    C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,    heterocyclyl, aryl, and heteroaryl is optionally substituted with    from 1 to 3 substituents independently selected at each occurrence    thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹⁶, 13 NR¹⁶, —NR¹⁶R¹⁷,    and phenyl which is optionally substituted 1-3 times with halogen,    C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR⁸, or —NR⁸R⁹;-   G is —NR⁸—CR⁹R¹⁰—CR¹¹R¹²—, —CR⁹R¹⁰—NR⁸—CR¹¹R¹²—, or    —CR⁹R¹⁰—CR¹¹R¹²—NR⁸—, with the proviso that when G is    —CR⁹R¹⁰—NR⁸—CR¹¹R¹²—, R² and R³ are not —C(O)NR¹³R¹⁴;-   X is CR¹⁸, C(R¹⁸)₂, N, or NR¹⁸;-   Y is CR¹⁸, C, or N;-   Z is C, CH, or N;-   L is —(CH₂)_(p)'O—, —(CH₂)_(p)—, —CH═CH—, or a bond;-   A is C, CH, or N;-   B is aryl, heteroaryl, heterocyclyl, or cycloalkyl, wherein each of    the aryl, heteroaryl, heterocyclyl, or cycloalkyl is optionally    substituted with from 1 to 3 substituents selected from the group    consisting of H, alkoxy, —S-alkyl, optionally substituted C₁-C₆    alkyl, halogen, —CF₃, and —CN;-   n is 0, 1, 2, or 3;-   p is from 1 to 4;-   q is 0, 1, or 2; and-   represents an optional double bond,-   or an oxide thereof, a pharmaceutically acceptable salt thereof, a    solvate thereof, or prodrug thereof.

As used above, and throughout the description of the invention, thefollowing terms, unless otherwise indicated, shall be understood to havethe following meanings If not defined otherwise herein, all technicaland scientific terms used herein have the same meaning as is commonlyunderstood by one of ordinary skill in the art to which this inventionbelongs. In the event that there is a plurality of definitions for aterm herein, those in this section prevail unless stated otherwise.

The term “alkyl” means an aliphatic hydrocarbon group which may bestraight or branched. When not otherwise restricted, the term refers toan alkyl of 20 or fewer carbons. Lower alkyl refers to alkyl groupshaving about 1 to about 6 carbon atoms in the chain. Branched means thatone or more lower alkyl groups such as methyl, ethyl or propyl areattached to a linear alkyl chain. Exemplary alkyl groups include methyl,ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, 3-pentyl, and thelike.

The term “alkenyl” means an aliphatic hydrocarbon group containing acarbon-carbon double bond and which may be straight or branched havingabout 2 to about 6 carbon atoms in the chain. Preferred alkenyl groupshave 2 to about 4 carbon atoms in the chain. Branched means that one ormore lower alkyl groups such as methyl, ethyl, or propyl are attached toa linear alkenyl chain. Exemplary alkenyl groups include ethenyl,propenyl, n-butenyl, and i-butenyl. In the present invention, the term“alkenyl” may also refer to a hydrocarbon chain having 2 to 6 carbonscontaining at least one double bond and at least one triple bond.

The term “alkynyl” means an aliphatic hydrocarbon group containing acarbon-carbon triple bond and which may be straight or branched havingabout 2 to about 6 carbon atoms in the chain. Preferred alkynyl groupshave 2 to about 4 carbon atoms in the chain. Branched means that one ormore lower alkyl groups such as methyl, ethyl, or propyl are attached toa linear alkynyl chain. Exemplary alkynyl groups include ethynyl,propynyl, n-butynyl, 2-butyryl, 3-methylbutynyl, and n-pentynyl.

The term “aryl” means an aromatic monocyclic or multi-cyclic(polycyclic) ring system of 6 to about 19 carbon atoms, preferably of 6to about 10 carbon atoms, and includes arylalkyl groups. The ring systemof the aryl group may be optionally substituted. Representative arylgroups of the present invention include, but are not limited to, groupssuch as phenyl, naphthyl, azulenyl, phenanthrenyl, anthracenyl,fluorenyl, pyrenyl, triphenylenyl, chrysenyl, and naphthacenyl.

The term “arylalkyl” means an alkyl residue attached to an aryl ring.Examples are benzyl, phenethyl, and the like.

The term “alkoxy” means groups of from 1 to 8 carbon atoms of astraight, branched, or cyclic configuration and combinations thereofattached to the parent structure through an oxygen. Examples includemethoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, andthe like. Lower-alkoxy refers to groups containing one to four carbons.For the purposes of the present patent application, alkoxy also includesmethylenedioxy and ethylenedioxy in which each oxygen atom is bonded tothe atom, chain, or ring from which the methylenedioxy or ethylenedioxygroup is pendant so as to form a ring. Thus, for example, phenylsubstituted by alkoxy may be, for example,

The term “compounds of the invention”, and equivalent expressions, aremeant to embrace compounds of general formula I as hereinbeforedescribed, which expression includes the prodrugs, the pharmaceuticallyacceptable salts, the oxides, the solvates, e.g. hydrates, and inclusioncomplexes of that compound, where the context so permits, as well as anystereoisomeric form, or a mixture of any such forms of that compound inany ratio. Inclusion complexes are described in Remington, The Scienceand Practice of Pharmacy, 19th Ed. 1:176-177 (1995), which is herebyincorporated by reference in its entirety. The most commonly employedinclusion complexes are those with cyclodextrins, and all cyclodextrincomplexes, natural and synthetic, are specifically encompassed withinthe claims. Thus, in accordance with some embodiments of the invention,a compound as described herein, including in the contexts ofpharmaceutical compositions, methods of treatment, and compounds per se,is provided as the salt form. Similarly, reference to intermediates,whether or not they themselves are claimed, is meant to embrace theirsalts, and solvates, where the context so permits. For the sake ofclarity, particular instances when the context so permits are sometimesindicated in the text, but these instances are purely illustrative andit is not intended to exclude other instances when the context sopermits.

The term “cycloalkyl” means a non-aromatic, saturated or unsaturated,mono- or multi-cyclic ring system of about 3 to about 7 carbon atoms,preferably of about 5 to about 7 carbon atoms, and which may include atleast one double bond. Exemplary cycloalkyl groups include, withoutlimitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclophenyl,anti-bicyclopropane, and syn-tricyclopropane.

The term “cycloalkylalkyl” means an cycloalkyl-alkyl-group in which thecycloalkyl and alkyl are as defined herein. Exemplary cycloalkylalkylgroups include cyclopropylmethyl and cyclopentylmethyl. The alkylradical and the cycloalkyl radical may be optionally substituted asdefined herein.

The term “haloalkyl” means both branched and straight-chain alkylsubstituted with one or more halogen, wherein the alkyl group is asherein described.

The term “halogen” means fluorine, chlorine, bromine, or iodine.

The term “heteroaryl” means an aromatic monocyclic or multi-cyclic ringsystem of about 5 to about 19 ring atoms, preferably about 5 to about 10ring atoms, in which one or more of the atoms in the ring system is/areelement(s) other than carbon, for example, nitrogen, oxygen, or sulfur.In the case of multi-cyclic ring system, only one of the rings needs tobe aromatic for the ring system to be defined as “heteroaryl”. Preferredheteroaryls contain about 5 to 6 ring atoms. The prefix aza, oxa, thia,or thio before heteroaryl means that at least a nitrogen, oxygen, orsulfur atom, respectively, is present as a ring atom. A nitrogen,carbon, or sulfur atom in the heteroaryl ring may be optionallyoxidized; the nitrogen may optionally be quaternized. Representativeheteroaryls include pyridyl, 2-oxo-pyridinyl, pyrimidinyl, pyridazinyl,pyrazinyl, triazinyl, furanyl, pyrrolyl, thiophenyl, pyrazolyl,imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl,oxadiazolyl, thiadiazolyl, tetrazolyl, indolyl, isoindolyl,benzofuranyl, benzothiophenyl, indolinyl, 2-oxoindolinyl,dihydrobenzofuranyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl,benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl,benzotriazolyl, benzo[1,3]dioxolyl, quinolinyl, isoquinolinyl,quinazolinyl, cinnolinyl, pthalazinyl, quinoxalinyl,2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,3]triazinyl,benzo[1,2,4]triazinyl, 4H-chromenyl, indolizinyl, quinolizinyl,6aH-thieno[2,3-d]imidazolyl, 1H-pyrrolo[2,3-b]pyridinyl,imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl,[1,2,4]triazolo[4,3-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl,thieno[2,3-b]furanyl, thieno[2,3-b]pyridinyl, thieno[3,2-b]pyridinyl,furo[2,3-b]pyridinyl, furo[3,2-b]pyridinyl, thieno[3,2-d]pyrimidinyl,furo[3,2-d]pyrimidinyl, thieno[2,3-b]pyrazinyl, imidazo[1,2-a]pyrazinyl,5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinyl,6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl,2-oxo-2,3-dihydrobenzo[d]oxazolyl, 3,3-dimethyl-2-oxoindolinyl,2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl,benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl,3,4-dihydro-2H-benzo[b][1,4]oxazinyl,5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl,[1,2,4]triazolo[4,3-a]pyrazinyl,3-oxo-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl, and the like.

As used herein, “heterocyclyl” or “heterocycle” refers to a stable 3- to18-membered ring (radical) which consists of carbon atoms and from oneto five heteroatoms selected from the group consisting of nitrogen,oxygen and sulfur. For purposes of this invention, the heterocycle maybe a monocyclic, or a polycyclic ring system, which may include fused,bridged, or spiro ring systems; and the nitrogen, carbon, or sulfuratoms in the heterocycle may be optionally oxidized; the nitrogen atommay be optionally quaternized; and the ring may be partially or fullysaturated. Examples of such heterocycles include, without limitation,azepinyl, azocanyl, pyranyl dioxanyl, dithianyl, 1,3-dioxolanyl,tetrahydrofuryl, dihydropyrrolidinyl, decahydroisoquinolyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, oxazolidinyl,oxiranyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl,pyrazolidinyl, thiazolidinyl, tetrahydropyranyl, thiamorpholinyl,thiamorpholinyl sulfoxide, and thiamorpholinyl sulfone. Furtherheterocycles and heteroaryls are described in Katritzky et al., eds.,Comprehensive Heterocyclic Chemistry: The Structure, Reactions,Synthesis and Use of Heterocyclic Compounds, Vol. 1-8, Pergamon Press,N.Y. (1984), which is hereby incorporated by reference in its entirety.

The term “method of treating” means amelioration or relief from thesymptoms and/or effects associated with the disorders described herein.As used herein, reference to “treatment” of a patient is intended toinclude prophylaxis.

The term “monocyclic” used herein indicates a molecular structure havingone ring.

The term “ optionally substituted” is used to indicate that a group mayhave a substituent at each substitutable atom of the group (includingmore than one substituent on a single atom), provided that thedesignated atom's normal valency is not exceeded and the identity ofeach substituent is independent of the others. In accordance with thepresent invention, up to three H atoms in each residue are replaced withalkyl, halogen, haloalkyl, hydroxy, loweralkoxy, carboxy, carboalkoxy(also referred to as alkoxycarbonyl), carboxamido (also referred to asalkylaminocarbonyl), cyano, carbonyl, nitro, amino, alkylamino,dialkylamino, mercapto, alkylthio, sulfoxide, sulfone, acylamino,amidino, phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, orheteroaryloxy. “Unsubstituted” atoms bear all of the hydrogen atomsdictated by their valency. When a substituent is keto (i.e., =0), thentwo hydrogens on the atom are replaced. Combinations of substituentsand/or variables are permissible only if such combinations result instable compounds; by “stable compound” or “stable structure” is meant acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

The term “pharmaceutical composition” means a composition comprising acompound of formula I and at least one component comprisingpharmaceutically acceptable carriers, diluents, adjuvants, excipients,or vehicles, such as preserving agents, fillers, disintegrating agents,wetting agents, emulsifying agents, suspending agents, sweeteningagents, flavoring agents, perfuming agents, antibacterial agents,antifungal agents, lubricating agents and dispensing agents, dependingon the nature of the mode of administration and dosage forms. As usedherein, the term “pharmaceutically acceptable carrier” is used to meanany carrier, diluent, adjuvant, excipient, or vehicle, as describedherein. Examples of suspending agents include ethoxylated isostearylalcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystallinecellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth,or mixtures of these substances. Prevention of the action ofmicroorganisms can be ensured by various antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, sorbic acid, andthe like. It may also be desirable to include isotonic agents, forexample sugars, sodium chloride, and the like. Prolonged absorption ofthe injectable pharmaceutical form can be brought about by the use ofagents delaying absorption, for example, aluminum monosterate andgelatin. Examples of suitable carriers, diluents, solvents, or vehiclesinclude water, ethanol, polyols, suitable mixtures thereof, vegetableoils (such as olive oil), and injectable organic esters such as ethyloleate. Examples of excipients include lactose, milk sugar, sodiumcitrate, calcium carbonate, and dicalcium phosphate. Examples ofdisintegrating agents include starch, alginic acids, and certain complexsilicates. Examples of lubricants include magnesium stearate, sodiumlauryl sulphate, talc, as well as high molecular weight polyethyleneglycols.

The term “pharmaceutically acceptable” means it is, within the scope ofsound medical judgment, suitable for use in contact with the cells ofhumans and lower animals without undue toxicity, irritation, allergicresponse and the like, and are commensurate with a reasonablebenefit/risk ratio.

The term “pharmaceutically acceptable dosage forms” means dosage formsof the compound of the invention, and includes, for example, tablets,dragees, powders, elixirs, syrups, liquid preparations, includingsuspensions, sprays, inhalants tablets, lozenges, emulsions, solutions,granules, capsules, and suppositories, as well as liquid preparationsfor injections, including liposome preparations. Techniques andformulations generally may be found in Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa., latest edition, which ishereby incorporated by reference in its entirety.

The term “pharmaceutically acceptable prodrugs” as used herein meansthose prodrugs of the compounds useful according to the presentinvention which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswith undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use, as well as the zwitterionic forms, where possible,of the compounds of the invention. The term “prodrug” means compoundsthat are rapidly transformed in vivo to yield the parent compound of theabove formula, for example by hydrolysis in blood. Commonly, theconversion of prodrug to drug occurs by enzymatic processes in the liveror blood of the mammal. Many of the compounds of the invention may bechemically modified without absorption into the systemic circulation,and in those cases, activation in vivo may come about by chemical action(as in the acid-catalyzed cleavage in the stomach) or through theintermediacy of enzymes and microflora in the gastrointestinal GI tract.Functional groups which may be rapidly transformed, by metaboliccleavage, in vivo form a class of groups reactive with the carboxylgroup of the compounds of this invention. They include, but are notlimited to, such groups as alkanoyl (such as acetyl, propionyl, butyryl,and the like), unsubstituted and substituted aroyl (such as benzoyl andsubstituted benzoyl), alkoxycarbonyl (such as ethoxycarbonyl),trialkylsilyl (such as trimethyl- and triethysilyl), monoesters formedwith dicarboxylic acids (such as succinyl), and the like. Because of theease with which the metabolically cleavable groups of the compoundsuseful according to this invention are cleaved in vivo, the compoundsbearing such groups act as pro-drugs. The compounds bearing themetabolically cleavable groups have the advantage that they may exhibitimproved bioavailability as a result of enhanced solubility and/or rateof absorption conferred upon the parent compound by virtue of thepresence of the metabolically cleavable group. A thorough discussion ofprodrugs is provided in the following: Design of Prodrugs, H. Bundgaard,ed., Elsevier (1985); Methods in Enzymology, K. Widder et al, Ed.,Academic Press, 42, p.309-396 (1985); A Textbook of Drug Design andDevelopment, Krogsgaard-Larsen and H. Bundgaard, ed., Chapter 5; “Designand Applications of Prodrugs,” p.113-191 (1991); Advanced Drug DeliveryReviews, H. Bundgaard, 8, p.1-38 (1992); Journal of PharmaceuticalSciences, 77:285 (1988); Nakeya et al, Chem. Pharm. Bull., 32:692(1984); Higuchi et al., “Pro-drugs as Novel Delivery Systems,” Vol. 14of the A.C.S. Symposium Series, and Bioreversible Carriers in DrugDesign, Edward B. Roche, ed., American Pharmaceutical Association andPergamon Press (1987), which are incorporated herein by reference intheir entirety. Examples of prodrugs include, but are not limited to,acetate, formate, and benzoate derivatives of alcohol and aminefunctional groups in the compounds of the invention.

The term “pharmaceutically acceptable salt” refers to salts preparedfrom pharmaceutically acceptable non-toxic acids or bases includinginorganic acids and bases and organic acids and bases. Suitablepharmaceutically acceptable acid addition salts for the compounds of thepresent invention include acetic, benzenesulfonic (besylate), benzoic,camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic,hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,succinic, sulfuric, tartaric acid, p-toluenesulfonic, and the like. Whenthe compounds contain an acidic side chain, suitable pharmaceuticallyacceptable base addition salts for the compounds of the presentinvention include metallic salts made from aluminum, calcium, lithium,magnesium, potassium, sodium and zinc or organic salts made from lysine,N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine), and procaine.Pharmaceutically acceptable salts include, but are not limited to, aminesalts, such as but not limited to N, N′dibenzylethylenediamine,chloroprocaine, choline, ammonia, diethanolamine and otherhydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine,N-benzylphenethylamine,1-para-chlorobenzyl-2-pyrrolidin-1′-ylmethyl-benzimidazole, diethylamineand other alkylamines, piperazine, and tris (hydroxymethyl)aminomethane; alkali metal salts, such as but not limited to lithium,potassium, and sodium; alkali earth metal salts, such as but not limitedto barium, calcium, and magnesium; transition metal salts, such as butnot limited to zinc; and other metal salts, such as but not limited tosodium hydrogen phosphate and disodium phosphate ; and also including,but not limited to, salts of mineral acids, such as but not limited tohydrochlorides and sulfates ; and salts of organic acids, such as butnot limited to acetates, lactates, malates, tartrates, citrates,ascorbates, succinates, butyrates, valerates and fumarates.Pharmaceutically acceptable esters include, but are not limited to,alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocyclylesters of acidic groups, including, but not limited to, carboxylicacids, phosphoric acids, phosphinic acids, sulfonic acids, sulfinicacids, and boronic acids. Pharmaceutical acceptable enol ethers include,but are not limited to, derivatives of formula C═C (OR) where R ishydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, orheterocyclyl. Pharmaceutically acceptable enol esters include, but arenot limited to, derivatives of formula C═C (OC(O)R) where R is hydrogen,alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl.Pharmaceutical acceptable solvates and hydrates are complexes of acompound with one or more solvent or water molecules, or 1 to about 100,or 1 to about 10, or one to about 2,3 or 4, solvent or water molecules.

The term “polycyclic” or “multi-cyclic” used herein indicates amolecular structure having two or more rings, including, but not limitedto, fused, bridged, or spiro rings.

Terminology related to “protecting”, “deprotecting,” and “protected”functionalities occurs throughout this application. Such terminology iswell understood by persons of skill in the art and is used in thecontext of processes which involve sequential treatment with a series ofreagents. In that context, a protecting group refers to a group which isused to mask a functionality during a process step in which it wouldotherwise react, but in which reaction is undesirable. The protectinggroup prevents reaction at that step, but may be subsequently removed toexpose the original functionality. The removal or “deprotection” occursafter the completion of the reaction or reactions in which thefunctionality would interfere. Thus, when a sequence of reagents isspecified, as it is in the processes of the invention, the person ofordinary skill can readily envision those groups that would be suitableas “protecting groups.” Suitable groups for that purpose are discussedin standard textbooks in the field of chemistry, such as Greene,Protective Groups in Organic Synthesis, John Wiley & Sons, New York(1991), which is hereby incorporated by reference in its entirety.

The term “solvate” refers to a compound of formula I in the solid state,wherein molecules of a suitable solvent are incorporated in the crystallattice. A suitable solvent for therapeutic administration isphysiologically tolerable at the dosage administered. Examples ofsuitable solvents for therapeutic administration are ethanol and water.When water is the solvent, the solvate is referred to as a hydrate. Ingeneral, solvates are formed by dissolving the compound in theappropriate solvent and isolating the solvate by cooling or using anantisolvent. The solvate is typically dried or azeotroped under ambientconditions.

The term “therapeutically effective amount” is meant to describe anamount of compound of the present invention effective producing thedesired therapeutic effect. Such amounts generally vary according to anumber of factors well within the purview of ordinarily skilled artisansgiven the description provided herein to determine and account for.These include, without limitation: the particular subject, as well asits age, weight, height, general physical condition, and medicalhistory, the particular compound used, as well as the carrier in whichit is formulated and the route of administration selected for it; and,the nature and severity of the condition being treated.

Compounds described herein may contain one or more asymmetric centersand may thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms. Each chiral center may be defined, in terms ofabsolute stereochemistry, as (R)- or (S)-. The present invention ismeant to include all such possible isomers, as well as mixtures thereof,including racemic and optically pure forms. Optically active (R)- and(S)-, (−)- and (+)-, or (D)- and (L)-isomers may be prepared usingchiral synthons or chiral reagents, or resolved using conventionaltechniques. When the compounds described herein contain olefinic doublebonds or other centers of geometric asymmetry, and unless specifiedotherwise, it is intended that the compounds include both E and Zgeometric isomers. Likewise, all tautomeric forms are also intended tobe included.

This invention also envisions the “quaternization” of any basicnitrogen-containing groups of the compounds disclosed herein. The basicnitrogen can be quaternized with any agents known to those of ordinaryskill in the art including, for example, lower alkyl halides, such asmethyl, ethyl, propyl and butyl chloride, bromides and iodides; dialkylsulfates including dimethyl, diethyl, dibutyl and diamyl sulfates; longchain halides such as decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides; and aralkyl halides including benzyl and phenethylbromides. Water or oil-soluble or dispersible products may be obtainedby such quaternization.

In the characterization of some of the substituents, it is recited thatcertain substituents may combine to form rings. Unless stated otherwise,it is intended that such rings may exhibit various degrees ofunsaturation (from fully saturated to fully unsaturated), may includeheteroatoms and may be substituted with lower alkyl or alkoxy.

In accordance with one embodiment of the present invention, compoundsrepresented by formula I above may be substituted derivatives either ofhexahydroazepino[4,3-b]indole, where G is —NR⁸—CH₂—CH₂—, ofhexahydroazepino[4,5-b]indole, where G is —CH₂—NR⁸—CH₂—, or ofhexahydroazepino[3,4-b]indole, where G is —CH₂—CH₂—NR⁸—.

In accordance with one embodiment of the present invention, R¹ is H. Inaccordance with another embodiment of the present invention, R¹ isoptionally substituted C₁-C₆ alkyl, for example, methyl. In accordancewith yet another embodiment of the present invention, R¹ is selectedfrom the group consisting of H, —S(O)_(q)R¹⁴, —C(O)R¹⁴, —C(O)NR¹³R¹⁴,C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl.

In accordance with one embodiment of the present invention, R²-R⁵ areeach independently selected from the group consisting of H andoptionally substituted C₁-C₆ alkyl.

In accordance with one embodiment of the present invention, R² and R³ orR⁴ and R⁵ combine to form an oxo group (carbonyl).

In accordance with one embodiment of the present invention, R⁶ is H,halogen, or optionally substituted C₁-C₆ alkyl.

In accordance with one embodiment of the present invention, R⁷ is H,halogen, or optionally substituted C₁-C₆ alkyl.

In accordance with one embodiment of the present invention, R⁸ is H. Inaccordance with another embodiment of the present invention, R⁸ isoptionally substituted C₁-C₆ alkyl, for example, methyl, ethyl, and2-propyl.

In accordance with one embodiment of the present invention, X is N, CH,or CH₂.

In accordance with one embodiment of the present invention, Y is N, C,or CH.

In accordance with one embodiment of the present invention, L is a bond.In accordance with another embodiment of the present invention, L is—CH₂—O—.

In accordance with one embodiment of the present invention, B is aryl.In one preferred embodiment, B is phenyl. In accordance with anotherembodiment of the present invention, B is heteroaryl. In one preferredembodiment, B is pyridinyl, for example pyridin-2-yl or pyridin-3-yl,pyridazinyl, for example, pyridazin-3-yl, or pyrimidinyl, for example,pyrimidin-5-yl.

As described herein, B may be optionally substituted. In one preferredembodiment, B is unsubstituted. In another preferred embodiment, B issubstituted with one substituent selected from trifluoromethyl, chloro,fluoro, methyl, and methanethio.

In accordance with one embodiment of the present invention, B isselected from the group consisting of phenyl, 4-(trifluoromethyl)phenyl,4-(methylthio)-phenyl, 5-(trifluoromethyl)pyridin-2-yl,2-(trifuloromethyl)-pyrimidin-5-yl, and6-(trifluoromethyl)pyridazin-3-yl, 5-fluoro-pyridin-2-yl,6-methylpyridin-3-yl, 6-(trifluoromethyl)pyridin-3-yl,5-chloro-pyridin-2-yl, 2,4-dichloro-phenyl, 2,4-difluoro-phenyl,4-chloro-phenyl, 4-chloro-2-fluoro-phenyl, 3,5-dichloro-pyridin-2-yl,4-fluoro-phenyl, pyridin-2-yl, and 3,5-difluoro-pyridin-2-yl.

Within these embodiments, the selection of a particular preferredsubstituent at any one of R¹-R¹⁸, X, Y, Z, L, A, and B does not affectthe selection of a substituent at any of the others of R¹-R¹⁸, X, Y, Z,L, A, and B. That is, preferred compounds provided herein have any ofthe preferred substituents at any of the positions.

In accordance with one embodiment of the present invention, the compoundhas the structure:

In accordance with one embodiment of the present invention, the compoundhas the structure

wherein R¹⁹, R²⁰, and R²¹ are individually selected from the groupconsisting of H, alkoxy, —S-alkyl, optionally substituted C₁-C₆ alkyl,halogen, —CF₃, and —CN.

In accordance with another embodiment of the present invention, thecompound has the structure

wherein R¹⁹, R²⁰, and R²¹ are individually selected from the groupconsisting of H, alkoxy, —S-alkyl, optionally substituted C₁-C₆ alkyl,halogen, —CF₃, and —CN.

In accordance with a further embodiment of the present invention, thecompound has the structure

wherein R¹⁹, R²⁰, and R²¹ are individually selected from the groupconsisting of H, alkoxy, —S-alkyl, optionally substituted C₁-C₆ alkyl,halogen, —CF₃, and —CN.

In accordance with one embodiment of the present invention, the compoundis selected from

In accordance with another embodiment of the present invention, thecompound is selected from

In accordance with yet another embodiment of the present invention, thecompound is selected from

Table 1, infra, lists compounds representative of embodiments of thepresent invention.

One embodiment of the present invention relates to pharmaceuticallyacceptable salts, or non-salt forms, of any of the compounds of formulaI described herein. In one embodiment, the salt is a HCl salt.

Single enantiomers, any mixture of enantiomers, including racemicmixtures, or diastereomers (both separated and as any mixtures) of thecompounds of the present invention are also included within the scope ofthe invention.

The scope of the present invention also encompasses active metabolitesof the present compounds.

The present invention also includes compounds of formula I, wherein oneor more of the atoms, e.g., C or H, are replaced by the correspondingradioactive isotopes of that atom (e.g., C replaced by ¹⁴C and Hreplaced by ³H), or a stable isotope of that atom (e.g., C replaced by¹³C or H replaced by ²H). Radioisotopes of hydrogen, carbon,phosphorous, fluorine iodine and chlorine include ³H, ¹⁴C, ³⁵S, ₁₈F,³²P, ³³P, ¹²⁵I, and ³⁶Cl, respectively. Compounds that contain thoseradioisotopes and/or other radioisotopes of other atoms are within thescope of this invention. Radiolabeled compounds described herein andprodrugs thereof can generally be prepared by methods well known tothose skilled in the art. Conveniently, such radiolabeled compounds canbe prepared by carrying out the procedures disclosed in the Examples andSchemes by substituting a readily available radiolabeled reagent for anon-radiolabeled reagent. Such compounds have a variety of potentialuses, e.g., as standards and reagents in determining the ability of apotential pharmaceutical to bind to neurotransmitter proteins. Inaddition, in the case of stable isotopes, such compounds may have thepotential to favorably modify the biological properties, e.g.,pharmacological and/or pharmacokinetic properties, of compounds offormula I. The details concerning selection of suitable sites forincorporating radioactive isotopes into the compounds are known to thoseskilled in the art.

Compounds of the present invention as described herein are useful asMCH-1 receptor antagonists. It may be found upon examination thatcompounds that are not presently excluded from the claims are notpatentable to the inventors in this application. In that case, theexclusion of species and genera in applicants' claims are to beconsidered artifacts of patent prosecution and not reflective of theinventors' concept or description of their invention. The invention, ina compound aspect, is all compounds of formula I, except those that arein the public's possession.

While it may be possible for compounds of formula I to be administeredas the raw chemical, it will often be preferable to present them as partof a pharmaceutical composition. Accordingly, another aspect of thepresent invention is a pharmaceutical composition containing atherapeutically effective amount of a compound of formula I, or apharmaceutically acceptable salt or solvate thereof, and apharmaceutically acceptable carrier. The carrier must be “acceptable” inthe sense of being compatible with the other ingredients of theformulation and not deleterious to the recipient thereof. Furthermore,when reference is made in an independent claim to a compound or apharmaceutically acceptable salt thereof, it will be understood thatclaims which depend from that independent claim which refer to such acompound also include pharmaceutically acceptable salts of the compound,even if explicit reference is not made to the salts.

Solid carriers suitable for use in the composition of the inventioninclude one or more substances which may also act as flavoring agents,lubricants, solubilizers, suspending agents, fillers, glidants,compression aides, binders, tablet-disintegrating agents, orencapsulating materials. In powders, the carrier may be a finely dividedsolid which is in admixture with a finely divided compound of formula I.In tablets, the formula I compound may be mixed with a carrier havingthe necessary compression properties in suitable proportions andcompacted in the shape and size desired. Said powders and tablets maycontain up to 99% by weight of the formula I compound. Solid carrierssuitable for use in the composition of the invention include calciumphosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch,gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidine, low melting waxes, and ion exchange resins.

Any pharmaceutically acceptable liquid carrier suitable for preparingsolutions, suspensions, emulsions, syrups and elixirs may be employed inthe composition of the invention. Compounds of formula I may bedissolved or suspended in a pharmaceutically acceptable liquid carriersuch as water, an organic solvent, or a pharmaceutically acceptable oilor fat, or a mixture thereof. Said liquid composition may contain othersuitable pharmaceutical additives such as solubilizers, emulsifiers,buffers, preservatives, sweeteners, flavoring agents, suspending agents,thickening agents, coloring agents, viscosity regulators, stabilizers,osmo-regulators, or the like. Examples of liquid carriers suitable fororal and parenteral administration include water (particularlycontaining additives as above, e.g., cellulose derivatives, preferablysodium carboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols, e.g., glycols) or their derivatives,or oils (e.g., fractionated coconut oil and arachis oil). For parenteraladministration the carrier may also be an oily ester such as ethyloleate or isopropyl myristate.

In one embodiment of the present invention, the pharmaceuticalcomposition further comprises one or more other therapeutic adjuncts,e.g., other compounds effective in the treatment of obesity, anxiety,depression, or non-alcoholic fatty liver disease, that are known topersons of skill in the art. Such other therapeutic adjuncts aredescribed below.

Another aspect of the present invention relates to a method of treatinga disease or condition which is susceptible to treatment with an MCH-1receptor antagonist. This method involves selecting a patient with adisease or condition which is susceptible to treatment with an MCH-1receptor antagonist and administering to the patient a therapeuticallyeffective amount of a compound of formula I or a pharmaceuticallyacceptable salt thereof.

Diseases or conditions which are susceptible to treatment with an MCH-1receptor antagonist in accordance with the present invention include,but are not limited to, obesity, general anxiety disorders, socialphobias, vertigo, obsessive-compulsive disorders, panic disorders,post-traumatic stress disorders, Parkinson's Disease Psychosis,schizophrenia, cognitive decline and defects in schizophrenia,Parkinson's Disease, Huntington's Chorea, presenile dementias,Alzheimer's Disease, psychological disorders, depression, substanceabuse disorders, dementia associated with neurodegenerative disease,cognition deficits, and epilepsy (see PCT Publication No. WO2007/010275, which is hereby incorporated by reference in its entirety).

As described above, the compounds of the present invention are useful asMCH-1 antagonists. As used in this invention, the term “antagonist”refers to a compound which binds to, and decreases the activity of, areceptor in the presence of an agonist.

As used herein, treatment means any manner in which one or more of thesymptoms of a disease or disorder are ameliorated or otherwisebeneficially altered. Treatment also encompasses any pharmaceutical useof the compositions herein, such as use for treating diseases ordisorders in which MCH-1 receptor activity is implicated.

In another embodiment of the present invention, the above method furtherinvolves administering a therapeutically effective amount of one or moretherapeutic adjuncts. Suitable therapeutic adjuncts include, but are notlimited to, anti-obesity and/or anorectic agents, anti-anxiety agents,anti-depression agents, and anti-non-alcoholic fatty liver diseaseagents.

Suitable anti-obesity and/or anorectic adjuncts include, but are notlimited to, phenylpropanolamine, ephedrine, pseudoephedrine,phentermine, a cholecystokinin-A (hereinafter referred to as CCK-A)agonist, a monoamine reuptake inhibitor (such as sibutramine), asympathomimetic agent, a serotonergic agent (such as dexfenfluramine orfenfluramine), a dopamine agonist (such as bromocriptine), amelanocyte-stimulating hormone receptor agonist or mimetic, amelanocyte-stimulating hormone analog, a cannabinoid receptor antagonistor inverse agonist, a melanin concentrating hormone receptor antagonist,a serotonin 5-HT₆ receptor antagonist, a serotonin 5-HT_(2C) receptoragonist, the OB protein (hereinafter referred to as “leptin”), a leptinanalog, a leptin receptor agonist, the amylin peptide, an amylin analog,an amylin receptor agonist, a neuropeptide Y receptor modulator, agalanin antagonist, or a GI lipase inhibitor or decreaser (such asorlistat). Other anorectic agents include bombesin agonists,dehydroepiandrosterone or analogs thereof, glucocorticoid receptoragonists and antagonists, orexin receptor antagonists, urocortin bindingprotein antagonists, agonists of the glucagon-like peptide-1 receptorsuch as Exendin and ciliary neurotrophic factors such as Axokine

Suitable anti-anxiety adjuncts include, but are not limited to, anallosteric modulator of the GABA_(A) receptor (such as diazepam,lorazepam, or alprazolam), a serotonin 5-HT_(1A) receptor partialagonist (such as buspirone), a selective serotonin reuptake inhibitor(SSRI, such as citalopram, escitalopram, fluoxetine, paroxetine, orsertraline), a serotonin-norepinephrine reuptake inhibitor (SNRI, suchas duloxetine or venlafaxine), a monoamine neurotransmitter reuptakeinhibitor of the tricyclic antidepressant (TCA) class (such asamitriptyline, desipramine, or imipramine), a combined serotoninreuptake inhibitor and 5-HT_(2C) antagonist (such as trazodone), and anH₁ receptor antagonist (such as hydroxyzine).

Suitable anti-depression adjuncts include, but are not limited to, aserotonin 5-HT_(1A) receptor partial agonist (such as buspirone), aselective serotonin reuptake inhibitor (SSRI, such as citalopram,escitalopram, fluoxetine, paroxetine, or sertraline), aserotonin-norepinephrine reuptake inhibitor (SNRI, such as duloxetine orvenlafaxine), a monoamine neurotransmitter reuptake inhibitor of thetricyclic antidepressant (TCA) class (such as amitriptyline,desipramine, or imipramine), a combined serotonin reuptake inhibitor and5-HT_(2C) antagonist (such as trazodone), a noradrenergic and specificserotonergic antidepressant (NaSSA, such as mianserin or mirtazapine), anorepinephrine reuptake inhibitor (NRI, such as atomoxetine orMazindol), a norepinephrine-dopamine reuptake inhibitor (NDRI, such asbupropion), and a monoamine oxidase inhibitor (MAOI, such asisocarboxazid or moclobemide).

Suitable anti-non-alcoholic fatty liver disease adjuncts include, butare not limited to, an AMP-activated protein kinase (AMPK) agonist (suchas metformin), a peroxisome proliferator-activated receptor (PPAR) gammaactivator (such as rosiglitazone, pioglitazone, or troglitazone), aHMG-CoA reductase inhibitor (such as atorvastatin or simvastatin), and aPDE4 inhibitor (such as pentoxifylline).

In one embodiment, the patient is a mammal. The term “mammal” is used inits dictionary sense. The term “mammal” includes, for example, mice,hamsters, rats, cows, sheep, pigs, goats, and horses, monkeys, dogs(e.g., Canis familiaris), cats, rabbits, guinea pigs, and primates,including humans.

The present invention also relates to a method of treating obesity in asubject in need of weight loss. This method involves selecting a patientin need of weight loss and administering to the patient atherapeutically effective amount of a compound of formula I or apharmaceutically acceptable salt thereof

This method further involves administering an anti-obesity adjunct, asdescribed above.

Yet another aspect of the present invention relates to a method oftreating obesity in a subject who has experienced weight loss. Thismethod involves selecting a patient who has experienced weight loss andadministering to the patient a therapeutically effective amount of acompound of formula I or a pharmaceutically acceptable salt thereof.

A further aspect of the present invention relates to a method oftreating anxiety. This method involves selecting a patient with anxietyand administering to the patient a therapeutically effective amount of acompound of formula I or a pharmaceutically acceptable salt thereof.

This method further involves administering an anti-anxiety adjunct, asdescribed above.

The present invention also relates to a method of treating depression.This method involves selecting a patient with depression andadministering to the patient a therapeutically effective amount of acompound of formula I or a pharmaceutically acceptable salt thereof.

This method further involves administering an anti-depression adjunct,as described above.

Another aspect of the present invention relates to a method of treatingnon-alcoholic fatty liver disease. This method involves selecting apatient who has non-alcoholic fatty liver disease and administering tothe patient a therapeutically effective amount of a compound of formulaI or a pharmaceutically acceptable salt thereof.

This method further involves administering an anti-non-alcoholic fattyliver disease adjunct, as described above.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination.

The present invention also relates to a process for preparation of aproduct compound of formula I:

This process involves treating a first intermediate of formula II:

wherein Q is a halogen, under conditions effective to form the productcompound of formula I, wherein R¹-R¹⁸, G, X, Y, Z, L, A, and B are asdefined above.

In one embodiment, treating involves reacting the first intermediatewith a second intermediate having the structure:

Compounds useful according to the invention may be prepared by theapplication or adaptation of known methods, by which is meant methodsused heretofore or described in the literature, for example, thosedescribed by Larock, Comprehensive Organic Transformations, Wiley-VCHpublishers, New York (1989), which is hereby incorporated by referencein its entirety.

A compound of formula I including a group containing one or morenitrogen ring atoms, may be converted to the corresponding compoundwherein one or more nitrogen ring atom of the group is oxidized to anN-oxide, preferably by reacting with a peracid, for example peraceticacid in acetic acid or m-chloroperoxybenzoic acid in an inert solventsuch as dichloromethane, at a temperature from about room temperature toreflux, preferably at elevated temperature.

In the reactions described hereinafter, it may be necessary to protectreactive functional groups, for example hydroxy, amino, imino, thio, orcarboxy groups, where these are desired in the final product, to avoidtheir unwanted participation in the reactions. Conventional protectinggroups may be used in accordance with standard practice and as describedabove.

The novel MCH-1 antagonists of formula I of this invention can beprepared by the methods illustrated in the general reaction schemes as,for example, described below, or by modifications thereof, using readilyavailable starting materials, reagents, and conventional synthesisprocedures. In these reactions, it is also possible to make use ofvariants that are known in the art but are not mentioned here. Althoughthe syntheses depicted herein may result in the preparation ofenantiomers having a particular stereochemistry, included within thescope of the present invention are compounds of formula I in anystereoisomeric form, and preparation of compounds of formula I instereoisomeric forms other than those depicted herein would be obviousto one of ordinary skill in the chemical arts based on the procedurespresented herein.

Synthetic Methods

Compounds of formula 3 (wherein R¹ is H or alkyl and R⁸ is a protectinggroup such as tert-butoxycarbonyl or benzyloxycarbonyl) can be preparedfrom compounds of formula 1 (or a salt thereof, wherein R¹ is H or alkyland Z is CH or N) and azepanone 2 (wherein R⁸ is a protecting group suchas tert-butoxycarbonyl or benzyloxycarbonyl) under heated acidicconditions. In the case where R¹ is H, optional alkylation or protectionof compound 3 can provide compounds of formula 3 wherein R¹ is alkyl ora protecting group such as tert-butoxycarbonyl, benzyloxycarbonyl orp-toluenesulfonyl. Optional removal of protecting group R⁸ and reductiveamination or alkylation can provide compounds of formula 3 wherein R⁸ isalkyl.

Compounds of formula 5 (wherein R¹ is H and Z is CH or N) can beprepared from compounds of formula 1 (or a salt thereof, wherein R¹ is Hand Z is CH or N) and cyclohexanone 4 under heated acidic conditions.Treatment of compounds of formula 5 under with an oxidizing agent suchas 2,3-dichloro-5,6-dicyano-1,4-benzoquinone can provide compounds offormula 6 (wherein R¹ is H and Z is CH or N). Optional N-alkylation orN-protection of compound 6 can provide compounds of formula 6 wherein R¹is alkyl or a protecting group such as tert-butoxycarbonyl,benzyloxycarbonyl or p-toluenesulfonyl. Compounds of formula 6 can beconverted to the corresponding oxime 7 and then heated under acidicconditions to provide compounds of formula 8 (wherein R¹ is H, alkyl ora protecting group such as tert-butoxycarbonyl, benzyloxycarbonyl orp-toluenesulfonyl and Z is CH or N). Treatment of compounds of formula 8with a reducing agent such as BH₃.THF under heated conditions canprovide compounds of formula 9 wherein R⁸ is H. Optional reductiveamination, alkylation, or protection can provide compounds of formula 9wherein R⁸ is alkyl or a protecting group such as tert-butoxycarbonyl orbenzyloxycarbonyl.

Alternatively, compounds of formula 5 can be treated with an oxidizingagent such as periodic acid to provide compounds of formula 10 (whereinR¹ is H and Z is CH or N). Optional N-alkylation or N-protection ofcompound 10 can provide compounds of formula 10 wherein R¹ is alkyl or aprotecting group such as tert-butoxycarbonyl, benzyloxycarbonyl orp-toluenesulfonyl. Compounds of formula 10 can be converted to thecorresponding oxime 11 and then heated under acidic conditions toprovide compounds of formula 12(wherein R¹ is H, alkyl or a protectinggroup such as tert-butoxycarbonyl, benzyloxycarbonyl orp-toluenesulfonyl and Z is CH or N). Treatement of compounds of formula12 with a reducing agent such as BH₃.THF under heated conditions canprovide compounds of formula 13 wherein R⁸ is H. Optional reductiveamination, alkylation, or protection can provide compounds of formula 13wherein R⁸ is alkyl or a protecting group such as tert-butoxycarbonyl orbenzyloxycarbonyl.

Compounds of formula 17 (wherein B is aryl, heteroaryl, heterocyclyl, orcycloalkyl; R¹⁹, R²⁰, and R²¹ are each independently selected from H,alkoxy, S-alkyl, alkyl, halo, —CF₃, and —CN; A is CH; X is CH; and L is—CH₂—O— or a bond) can be prepared by treating compounds of formula 14(wherein X¹ is chlorine, bromine or iodine; A is CH; and X is CH) withcompounds of formula 15 (wherein B is aryl, heteroaryl, heterocyclyl, orcycloalkyl; R¹⁹, R²⁰, and R²¹ are each independently selected from H,—O-alkyl, alkyl, halo, —CF₃, and —CN; Z¹ is B(OH)₂, B(OR²²)₂, SnR²² ₃ orthe like and R²² is alkyl), a catalyst such as palladium(0), and a basesuch as potassium carbonate to give compounds of formula 16, wherein Lis a direct bond. Alternatively, in the case where Z¹ is —CH₂—OH and Bis aryl, heteroaryl, heterocyclyl, or cycloalkyl, compounds of formula15 can be treated with a base such as sodium hydride and compounds offormula 14 under heated conditions to give compounds of formula 16,wherein L is —CH₂—O—. In turn, compounds of formula 16 can be treatedwith acetic anhydride under heated conditions followed by methanol andwater or methanol and sodium hydroxide under ambient to heatedconditions to provide compounds of formula 17, wherein L is —CH₂O— or adirect bond.

Alternatively, compounds of formula 17 (wherein B is aryl, heteroaryl,heterocyclyl, or cycloalkyl; R¹⁹, R^(20,) and R²¹ are each independentlyselected from H, alkoxy, —S-alkyl, alkyl, halo, —CF₃, and —CN; A is CHor N; X is CH; and L is —CH₂—CH₂—, or a bond) can be prepared bytreating compounds of formula 18 (wherein X¹ is chlorine, bromine oriodine; X² is —O—CH₃ or chlorine; A is CH or N; and X is CH) withcompounds of formula 15 (wherein Z¹ is —CH═CH—B(OR²²)², B(OH)₂,B(OR²²)₂, SnR²² ₃ or the like and R²² is alkyl), a catalyst such aspalladium(0), and a base such as potassium carbonate to give compoundsof formula 19, wherein L is —CH═CH— or a direct bond, in accordance withZ¹. In the case where L is —CH═CH—, compounds of formula 19 can betreated with palladium on carbon under an atmosphere of hydrogen to givecompounds of formula 19, wherein L is —CH₂CH₂—. Alternatively, in thecase where Z¹ is —CH₂—OH, compounds of formula 18 can be treated withcompounds of formula 15, a catalyst such as copper iodide, a ligand suchas 3,4,7,8-tetramethylphenanthroline and a base such as cesium carbonateunder heated conditions to give compounds of formula 19, wherein L is—CH₂—O—. In turn, when L is —CH₂—CH₂—, —CH₂—O— or a direct bond,compounds of formula 19 can be heated under acid conditions to providecompounds of formula 17, wherein L is —CH₂—CH₂—, —CH₂—O— or a directbond, respectively.

Alternatively, compounds of formula 17 (wherein B is aryl, heteroaryl,heterocyclyl, or cycloalkyl; R¹⁹, R²⁰, and R²¹ are each independentlyselected from H, alkoxy, S-alkyl, alkyl, halo, —CF₃, and —CN; A is CH; Xis N; and L is —CH₂—O— or a bond) can be prepared from compounds offormula 20 (wherein A is CH; X is N; and R²³ is a protecting group suchas tetrahydropyran-2-yl). The hydroxyl group on compound 20 can beconverted to an appropriate activating group to give compounds offormula 21. In the case where Z² is triflate, compounds of formula 20can be treated with trifluoromethylsulfonic anhydride or N-phenyltrifluoromethanesulfonamide and a base such as triethylamine, pyridineor lithium bis(trimethylsilyl)amide under cooled conditions to givecompounds of formula 21. Treatment of compounds of formula 21 withcompounds of formula 15 (wherein B is aryl, heteroaryl, heterocyclyl, orcycloalkyl; R¹⁹, R²⁰, and R²¹ are each independently selected from H,alkoxy, S-alkyl, alkyl, halo, —CF₃, and —CN; Z¹ is B(OH)₂, B(OR²²)₂,SnR²² ₃ or the like, and R²² is alkyl), a catalyst such as palladium(0),and a base such as potassium carbonate under heated conditions canprovide compounds of formula 22, wherein L is a direct bond.Alternatively, in the case where Z¹ is —CH₂—Br, compounds of formula 15can be treated with compounds of formula 20 and a base such as aspotassium carbonate to give compounds of formula 22, wherein L is—CH₂—O—. Removal of the protecting group R²³ on compound 22 can providecompounds of formula 17, wherein L is —CH₂—O— or a bond.

Compounds of formula 24 (wherein B is aryl, heteroaryl, heterocyclyl, orcycloalkyl; R¹⁹, R²⁰, and R²¹ are each independently selected from H,alkoxy, —S-alkyl, alkyl, halo, —CF₃, and —CN; L is —CH₂—CH₂—, —CH₂—O— ora bond; A is CH or N; X is CH or N; Z is CH or N; G is —NR⁸—CH₂—CH₂—,—CH₂—NR⁸—CH₂— or —CH₂—CH₂—NR⁸—; R⁸ is H, alkyl, or a protecting groupsuch as tert-butoxycarbonyl or benzyloxycarbonyl; R¹ is alkyl or aprotecting group such as tert-butoxycarbonyl, benzyloxycarbonyl orp-toluenesulfonyl; and R², R³, R⁴ and R⁵ are each H or, in the casewhere G is —NR⁸—CH₂—CH₂—, R⁴ and R⁵ can combine to form a carbonyloxygen) can be prepared by treating compounds of formula 23 (wherein Zis CH or N; G is —NR⁸—CH₂—CH₂—, —CH₂—NR⁸—CH₂—, or —CH₂—CH₂—NR⁸—, R⁸ isH, alkyl, or a protecting group such as tert-butoxycarbonyl orbenzyloxycarbonyl; R¹ is alkyl or a protecting group such astert-butoxycarbonyl, benzyloxycarbonyl or p-toluenesulfonyl; and R², R³,R⁴ and R⁵ are each H or, in the case where G is —NR⁸—CH₂—CH₂—, R⁴ and R⁵can combine to form a carbonyl oxygen) under heated conditions with acatalyst such as copper iodide, a ligand such astrans-1,2-diaminocyclohexane or 8-hydroxyquinoline, a base such aspotassium carbonate, cesium carbonate or potassium phosphate andcompounds of formula 17 (wherein B is aryl, heteroaryl, heterocyclyl, orcycloalkyl; R¹⁹, R^(20,) and R²¹ are each independently selected from H,alkoxy, —S-alkyl, alkyl, halo, —CF₃, and —CN; L is —CH₂—CH₂—, —CH₂—O— ora bond; A is CH or N; and X is CH or N). In the case where R⁸ is aprotecting group, the protecting group can be removed to give compoundsof formula 24 wherein R⁸ is H. In the case where R⁸ is H, reductiveamination or alkylation can provide compounds of formula 24, wherein R⁸is an alkyl group. Additionally, in the case where R¹ is a protectinggroup, the protecting group can be removed to give compounds of formula24 wherein R¹ is H.

Compounds of formula 25 (wherein A is CH or N; X is CH or N; Z is CH orN; G is —NR⁸—CH₂—CH₂—, —CH₂—NR⁸—CH₂—, or —CH₂—CH₂—NR⁸—; R⁸ is H, alkyl,or a protecting group such as tert-butoxycarbonyl or benzyloxycarbonyl;R¹ is alkyl or a protecting group such as tert-butoxycarbonyl,benzyloxycarbonyl or p-toluenesulfonyl; and R², R³, R⁴ and R⁵ are each Hor, in the case where G is —NR⁸—CH₂—CH₂—, R⁴ and R⁵ can combine to forma carbonyl oxygen) can be treated with hydrogen and a catalyst such aspalladium on carbon to provide compounds of formula 26. The hydroxylgroup on compounds of formula 26 can be converted to an appropriateactivating group to give compounds of formula 27. In the case where Z²is triflate, compounds of formula 26 can be treated withtrifluoromethylsulfonic anhydride or N-phenyltrifluoromethanesulfonamide and a base such as pyridine or lithiumbis(trimethylsilyl)amide under cooled conditions to give compounds offormula 27. Treatment of compounds of formula 27 with compounds offormula 15 (wherein B is aryl, heteroaryl, heterocyclyl, or cycloalkyl;R¹⁹, R²⁰, R²¹ are each independently selected from H, alkoxy, —S-alkyl,alkyl, halo, —CF₃, and —CN; Z¹ is —CH═CH—B(OR²²)₂, B(OH)₂, B(OR²²)₂,SnR²² ₃ or the like and R²² is alkyl), a catalyst such as palladium(0),and a base such as potassium carbonate under heated conditions canprovide compounds of formula 24, wherein L is —CH═CH— or a direct bond.In the case where L is —CH═CH—, compounds of formula 24 can be treatedwith palladium on carbon under an atmosphere of hydrogen to givecompounds of formula 24, where L is —CH₂CH₂—.

Compounds of formula 29 (wherein B is aryl, heteroaryl, heterocyclyl, orcycloalkyl; R¹⁹, R²⁰, and R²¹ are each independently selected from H,alkoxy, —S-alkyl, alkyl, halo, —CF₃, and —CN; and L is —CH₂—CH₂-) can beprepared by treating piperazin-2-one 28 with compounds of formula 15(wherein Z¹ is —CH₂—CH₂—X¹; and X¹ is a leaving group such as chlorine,bromine, iodine or the like) and a base such as di-isopropylamine togive compounds of formula 29, wherein L is —CH₂—CH₂—.

Compounds of formula 30 (wherein B is aryl, heteroaryl, heterocyclyl, orcycloalkyl; R¹⁹, R²⁰, and R²¹ are each independently selected from H,alkoxy, —S-alkyl, alkyl, halo, —CF₃, and —CN; L is —CH₂—CH₂—; Z is CH orN; G is —NR⁸—CH₂—CH₂—, —CH₂—NR⁸—CH₂— or —CH₂—CH₂—NR⁸—; R⁸ is H, alkyl,or a protecting group such as tert-butoxycarbonyl or benzyloxycarbonyl;R¹ is alkyl or a protecting group such as tert-butoxycarbonyl,benzyloxycarbonyl or p-toluenesulfonyl; and R², R³, R⁴ and R⁵ are each Hor, in the case where G is —NR⁸—CH₂—CH₂—, R⁴ and R⁵ can combine to forma carbonyl oxygen) can be prepared by treating compounds of formula 23(wherein Z is CH or N; G is —NR⁸—CH₂—CH₂—, —CH₂—NR⁸—CH₂—, or—CH₂—CH₂—NR⁸—, R⁸ is H, alkyl, or a protecting group such astert-butoxycarbonyl or benzyloxycarbonyl; R¹ is alkyl or a protectinggroup such as tert-butoxycarbonyl, benzyloxycarbonyl orp-toluenesulfonyl; and R², R³, R⁴ and R⁵ are each H or, in the casewhere G is —NR⁸—CH₂—CH₂—, R⁴ and R⁵ can combine to form a carbonyloxygen) under heated conditions with a catalyst such as copper iodide, aligand such as trans-1,2-bis(methylamino)cyclohexane or8-hydroxyquinoline, a base such as potassium carbonate, cesium carbonateor potassium phosphate and compounds of formula 29 (wherein B is aryl,heteroaryl, heterocyclyl, or cycloalkyl; R¹⁹, R²⁰, and R²¹ are eachindependently selected from H, alkoxy, —S-alkyl, alkyl, halo, —CF₃, and—CN; and L is —CH₂—CH₂—). In the case where R⁸ is a protecting group,the protecting group can be removed to give compounds of formula 30wherein R⁸ is H. In the case where R⁸ is H, reductive amination oralkylation can provide compounds of formula 30, wherein R⁸ is an alkylgroup. Additionally, in the case where R¹ is a protecting group, theprotecting group can be removed to give compounds of formula 30 whereinR¹ is H.

The present invention provides compositions containing the compoundsdescribed herein, including, in particular, pharmaceutical compositionscomprising therapeutically effective amounts of the compounds andpharmaceutically acceptable carriers.

It is a further object of the present invention to provide kits having aplurality of active ingredients (with or without carrier) which,together, may be effectively utilized for carrying out the novelcombination therapies of the invention.

It is another object of the invention to provide a novel pharmaceuticalcomposition which is effective, in and of itself, for utilization in abeneficial combination therapy because it includes a plurality of activeingredients which may be utilized in accordance with the invention.

The present invention also provides kits or single packages combiningone or more active ingredients useful in treating the disease. A kit mayprovide (alone or in combination with a pharmaceutically acceptablediluent or carrier) the compounds of formula I and an additional activeingredient (alone or in combination with diluent or carrier), asdescribed above.

The products according to the present invention may be presented informs permitting administration by the most suitable route and theinvention also relates to pharmaceutical compositions containing atleast one product according to the invention which are suitable for usein human or veterinary medicine. These compositions may be preparedaccording to the customary methods, using one or more pharmaceuticallyacceptable adjuvants or excipients. The adjuvants comprise, inter alia,diluents, sterile aqueous media, and the various non-toxic organicsolvents. The compositions may be presented in the form of tablets,pills, granules, powders, aqueous solutions or suspensions, injectablesolutions, elixirs or syrups, and can contain one or more agents chosenfrom the group comprising sweeteners, flavorings, colorings, orstabilizers in order to obtain pharmaceutically acceptable preparations.

The formulations of compounds of formula I include those suitable fororal, parenteral (including subcutaneous, intradermal, intramuscular,intraperitoneal, intravenous, and intraarticular), rectal, colonic, andtopical (including dermal, buccal, nasal, sublingual, and intraocular)administration. The most suitable route may depend upon the conditionand disorder of the recipient. The formulations may conveniently bepresented in unit dosage form and may be prepared by any of the methodswell known in the art of pharmacy. Such methods include the step ofbringing into association a compound of formula I or a pharmaceuticallyacceptable salt or solvate thereof (“active ingredient”) with thecarrier, which constitutes one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing into association the active ingredient with liquid carriers orfinely divided solid carriers or both and then, if necessary, shapingthe product into the desired formulation.

Formulations suitable for oral administration may be presented asdiscrete units such as capsules, cachets, or tablets each containing apredetermined amount of the active ingredient; as a powder or granules;as a solution or a suspension in an aqueous liquid or a non-aqueousliquid; or as an oil-in-water liquid emulsion or a water-in-oil liquidemulsion. The active ingredient may also be presented as a bolus,electuary, or paste.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed with abinder, lubricant, inert diluent, lubricating, surface active, ordispersing agent. Molded tablets may be made by molding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent. The tablets may optionally be coated or scored and maybe formulated so as to provide sustained, delayed, or controlled releaseof the active ingredient therein.

The pharmaceutical compositions may include a “pharmaceuticallyacceptable inert carrier”, and this expression is intended to includeone or more inert excipients, which include starches, polyols,granulating agents, microcrystalline cellulose, diluents, lubricants,binders, disintegrating agents, and the like. If desired, tablet dosagesof the disclosed compositions may be coated by standard aqueous ornonaqueous techniques, “Pharmaceutically acceptable carrier” alsoencompasses controlled release means.

Pharmaceutical compositions may also optionally include othertherapeutic ingredients, anti-caking agents, preservatives, sweeteningagents, colorants, flavors, desiccants, plasticizers, dyes, and thelike. Any such optional ingredient must be compatible with the compoundof formula I to insure the stability of the formulation. The compositionmay contain other additives as needed, including for example lactose,glucose, fructose, galactose, trehalose, sucrose, maltose, raffinose,maltitol, melezitose, stachyose, lactitol, palatinite, starch, xylitol,mannitol, myoinositol, and the like, and hydrates thereof, and aminoacids, for example alanine, glycine and betaine, and peptides andproteins, for example albumen.

Examples of excipients for use as the pharmaceutically acceptablecarriers and the pharmaceutically acceptable inert carriers and theaforementioned additional ingredients include, but are not limited tobinders, fillers, disintegrants, lubricants, anti-microbial agents, andcoating agents.

The dose range for adult humans is generally from 0.001 mg to 10 g/dayorally. Tablets or other forms of presentation provided in discreteunits may conveniently contain an amount of compound of formula I whichis effective at such dosage or as a multiple of the same, for instance,units containing 5 mg to 500 mg, usually around 10 mg to 200 mg. Theprecise amount of compound administered to a patient will be theresponsibility of the attendant physician. It will be understood,however, that the specific dose level for any particular patient willdepend upon a variety of factors including the activity of the specificcompound employed, the age, body weight, general health, sex, diet timeof administration, route of administration, rate of excretion, drugcombination and the severity of the particular disease undergoingtherapy.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, aformulation intended for the oral administration of humans may vary fromabout 5 to about 95% of the total composition.

A dosage unit (e.g. an oral dosage unit) can include from, for example,0.01 to 0.1 mg, 1 to 30 mg, 1 to 40 mg, 1 to 100 mg, 1 to 300 mg, 1 to500 mg, 2 to 500 mg, 3 to 100 mg, 5 to 20 mg, 5 to 100 mg (e.g. 0.01 mg,1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 25 mg, 30mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80mg, 85 mg, 90 mg, 95 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg,400 mg, 450 mg, 500 mg) of a compound described herein.

The products according to the present invention may be administered asfrequently as necessary in order to obtain the desired therapeuticeffect. Some patients may respond rapidly to a higher or lower dose andmay find much weaker maintenance doses adequate. For other patients, itmay be necessary to have long-term treatments at the rate of 1 to 4doses per day, in accordance with the physiological requirements of eachparticular patient. Generally, the active product may be administeredorally 1 to 4 times per day. It goes without saying that, for otherpatients, it will be necessary to prescribe not more than one or twodoses per day.

For additional information about pharmaceutical compositions and theirformulation, see, for example, Remington, The Science and Practice ofPharmacy, 20^(th) Edition (2000), which is hereby incorporated byreference in its entirety.

The compounds of formula 1 can be administered, e.g., by intravenousinjection, intramuscular injection, subcutaneous injection,intraperitoneal injection, topical, sublingual, intraarticular (in thejoints), intradermal, buccal, ophthalmic (including intraocular),intranasally (including using a cannula), or by other routes. Thecompounds of formula I can be administered orally, e.g., as a tablet orcachet containing a predetermined amount of the active ingredient, gel,pellet, paste, syrup, bolus, electuary, slurry, capsule, powder,granules, as a solution or a suspension in an aqueous liquid or anon-aqueous liquid, as an oil-in-water liquid emulsion or a water-in-oilliquid emulsion, via a micellar formulation (see, e.g. PCT PublicationNo. WO 97/11682, which is hereby incorporated by reference in itsentirety) via a liposomal formulation (see, e.g., European Patent EP736299 and PCT Publication Nos. WO 99/59550 and WO 97/13500, which arehereby incorporated by reference in their entirety), via formulationsdescribed in PCT Publication No. WO 03/094886, which is herebyincorporated by reference in its entirety, or in some other form. Thecompounds of formula I can also be administered transdermally (i.e. viareservoir-type or matrix-type patches, microneedles, thermal poration,hypodermic needles, iontophoresis, electroporation, ultrasound or otherforms of sonophoresis, jet injection, or a combination of any of thepreceding methods (Prausnitz et al., Nature Reviews Drug Discovery 3:115(2004), which is hereby incorporated by reference in its entirety)). Thecompounds can be administered locally, for example, at the site ofinjury to an injured blood vessel. The compounds can be coated on astent. The compounds can be administered using high-velocity transdermalparticle injection techniques using the hydrogel particle formulationdescribed in U.S. Patent Publication No. 20020061336, which is herebyincorporated by reference in its entirety. Additional particleformulations are described in PCT Publication Nos. WO 00/45792, WO00/53160, and WO 02/19989, which are hereby incorporated by reference intheir entirety. An example of a transdermal formulation containingplaster and the absorption promoter dimethylisosorbide can be found inPCT Publication No. WO 89/04179, which is hereby incorporated byreference in its entirety. PCT Publication No. WO 96/11705, which ishereby incorporated by reference in its entirety, provides formulationssuitable for transdermal administration.

The compounds can be administered in the form a suppository or by othervaginal or rectal means. The compounds can be administered in atransmembrane formulation as described in PCT Publication No. WO90/07923, which is hereby incorporated by reference in its entirety. Thecompounds can be administered non-invasively via the dehydratedparticles described in U.S. Pat. No. 6,485,706, which is herebyincorporated by reference in its entirety. The compound can beadministered in an enteric-coated drug formulation as described in PCTPublication No. WO 02/49621, which is hereby incorporated by referencein its entirety. The compounds can be administered intranasaly using theformulation described in U.S. Pat. No. 5,179,079, which is herebyincorporated by reference in its entirety. Formulations suitable forparenteral injection are described in PCT Publication No. WO 00/62759,which is hereby incorporated by reference in its entirety. The compoundscan be administered using the casein formulation described in U.S.Patent Publication No. 20030206939 and PCT Publication No. WO 00/06108,which are hereby incorporated by reference in their entirety. Thecompounds can be administered using the particulate formulationsdescribed in U.S. Patent Application Publication No. 20020034536, whichis hereby incorporated by reference in its entirety.

The compounds, alone or in combination with other suitable components,can be administered by pulmonary route utilizing several techniquesincluding but not limited to intratracheal instillation (delivery ofsolution into the lungs by syringe), intratracheal delivery ofliposomes, insufflation (administration of powder formulation by syringeor any other similar device into the lungs) and aerosol inhalation.Aerosols (e.g., jet or ultrasonic nebulizers, metered-dose inhalers(MDIs), and dry-Powder inhalers (DPIs)) can also be used in intranasalapplications. Aerosol formulations are stable dispersions or suspensionsof solid material and liquid droplets in a gaseous medium and can beplaced into pressurized acceptable propellants, such ashydrofluoroalkanes (HFAs, i.e. HFA-134a and HFA-227, or a mixturethereof), dichlorodifluoromethane (or other chlorofluorocarbonpropellants such as a mixture of Propellants 11, 12, and/or 114),propane, nitrogen, and the like. Pulmonary formulations may includepermeation enhancers such as fatty acids, and saccharides, chelatingagents, enzyme inhibitors (e.g., protease inhibitors), adjuvants (e.g.,glycocholate, surfactin, span 85, and nafamostat), preservatives (e.g.,benzalkonium chloride or chlorobutanol), and ethanol (normally up to 5%but possibly up to 20%, by weight). Ethanol is commonly included inaerosol compositions as it can improve the function of the meteringvalve and in some cases also improve the stability of the dispersion.

Pulmonary formulations may also include surfactants which include butare not limited to bile salts and those described in U.S. Pat. No.6,524,557 and references therein, which is hereby incorporated byreference in its entirety. The surfactants described in U.S. Pat. No.6,524,557, which is hereby incorporated by reference in its entirety,e.g., a C₈-C₁₆ fatty acid salt, a bile salt, a phospholipid, or alkylsaccharide are advantageous in that some of them also reportedly enhanceabsorption of the compound in the formulation.

Also suitable in the invention are dry powder formulations comprising atherapeutically effective amount of active compound blended with anappropriate carrier and adapted for use in connection with a dry-powderinhaler. Absorption enhancers that can be added to dry powderformulations of the present invention include those described in U.S.Pat. No. 6,632,456, which is hereby incorporated by reference in itsentirety. PCT Publication No. WO 02/080884, which is hereby incorporatedby reference in its entirety, describes new methods for the surfacemodification of powders. Aerosol formulations may include U.S. Pat. No.5,230,884, U.S. Pat. No. 5,292,499, PCT Publication No. WO 017/8694, PCTPublication No. WO 01/78696, U.S. Patent Application Publication No.2003019437, U.S. Patent Application Publication No. 20030165436, and PCTPublication No. WO 96/40089 (which includes vegetable oil), which arehereby incorporated by reference in their entirety. Sustained releaseformulations suitable for inhalation are described in U.S. PatentApplication Publication Nos. 20010036481A1, 20030232019A1, and20040018243A1 as well as in PCT Publication Nos. WO 01/13891, WO02/067902, WO 03/072080, and WO 03/079885, which are hereby incorporatedby reference in their entirety.

Pulmonary formulations containing microparticles are described in PCTPublication No. WO 03/015750, U.S. Patent Application Publication No.20030008013, and PCT Publication No. WO 00/00176, which are herebyincorporated by reference in their entirety. Pulmonary formulationscontaining stable glassy state powder are described in U.S. PatentApplication Publication No. 20020141945 and U.S. Pat. No. 6,309,671,which are hereby incorporated by reference in their entirety. Otheraerosol formulations are described in EP 1338272A1, PCT Publication No.WO 90/09781, U.S. Pat. No. 5,348,730, U.S. Pat. No. 6,436,367, PCTPublication No. WO 91/04011, and U.S. Pat. No. 6,294,153, which arehereby incorporated by reference in their entirety, and U.S. Pat. No.6,290,987, which is hereby incorporated by reference in its entirety,describes a liposomal based formulation that can be administered viaaerosol or other means.

Powder formulations for inhalation are described in U.S. PatentApplication Publication No. 20030053960 and PCT Publication No. WO01/60341, which are hereby incorporated by reference in their entirety.The compounds can be administered intranasally as described in U.S.Patent Application Publication No. 20010038824, which is herebyincorporated by reference in its entirety.

Solutions of medicament in buffered saline and similar vehicles arecommonly employed to generate an aerosol in a nebulizer. Simplenebulizers operate on Bernoulli's principle and employ a stream of airor oxygen to generate the spray particles. More complex nebulizersemploy ultrasound to create the spray particles. Both types are wellknown in the art and are described in standard textbooks of pharmacysuch as Sprowls' American Pharmacy and Remington's The Science andPractice of Pharmacy, which are hereby incorporated by reference intheir entirety.

Other devices for generating aerosols employ compressed gases, usuallyhydrofluorocarbons and chlorofluorocarbons, which are mixed with themedicament and any necessary excipients in a pressurized container,these devices are likewise described in standard textbooks such asSprowls and Remington, which are hereby incorporated by reference intheir entirety.

Compounds of formula I can be incorporated into a liposome to improvehalf-life. Compounds of formula I can also be conjugated to polyethyleneglycol (PEG) chains. Methods for pegylation and additional formulationscontaining PEG-conjugates (i.e. PEG-based hydrogels, PEG modifiedliposomes) can be found in Harris et al., Nature Reviews Drug Discovery,2:214-221 (2003) and the references therein, which are herebyincorporated by reference in their entirety. Compounds of formula I canalso be administered via a nanocochleate or cochleate delivery vehicle(BioDelivery Sciences International, Raleigh, N.C.). Compounds offormula I can also be delivered using nanoemulsion formulations.

Examples

The Examples set forth below are for illustrative purposes only and arenot intended to limit, in any way, the scope of the present invention.

Example 1 Analytical Methods and Materials

Unless otherwise noted, reagents and solvents were used as received fromcommercial suppliers. Proton nuclear magnetic resonance (NMR) spectrawere obtained on Bruker spectrometers at 300, 400 or 500 MHz. Spectraare given in ppm (6) and coupling constants, J, are reported in Hertz.Tetramethylsilane (TMS) was used as an internal standard. Mass spectrawere collected using either a Finnigan LCQ Duo LCMS ion trapelectrospray ionization (ESI) or a mass Varian 1200L single quadrapolemass spectrometer (ESI). High performance liquid chromatograph (HPLC)analyses were obtained using a Luna C18(2) column (250×4.6 mm,Phenomenex) or a Gemini C18 column (250×4.6 mm, Phenomenex) with UVdetection at 254 nm or 223 nm using a standard solvent gradient program(Method A, Method B or Method C).

Method A:

Time Flow (min) (mL/min) % A % B 0.0 1.0 90.0 10.0 20 1.0 10.0 90.0 301.0 10.0 90.0 A = Water with 0.05% Trifluoroacetic Acid B = Acetonitrilewith 0.05% Trifluoroacetic Acid

Method B:

Time Flow (min) (mL/min) % A % B 0.0 1.0 98.0 2.0 20 1.0 2.0 98.0 25 1.02.0 98.0 A = Water with 0.025% Trifluoroacetic Acid B = Acetonitrilewith 0.025% Trifluoroacetic Acid

Method C:

Time Flow (min) (mL/min) % A % B 0.0 1.0 98.0 2.0 20 1.0 10.0 90.0 301.0 10.0 90.0 A = Water with 0.025% Trifluoroacetic Acid B =Acetonitrile with 0.025% Trifluoroacetic Acid

Example 2 Preparation of1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-onedihydrochloride a) tert-Butyl8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate

A solution of 3-bromophenylhydrazine hydrochloride (8.070 g, 36.03 mmol)and tert-butyl 4-oxoazepane-1-carboxylate (7.710 g, 36.03 mmol) in 15:2EtOH/(12 N HCl solution) (68 mL) was stirred at reflux for 28 h. Thesolution was concentrated under reduced pressure to afford a residue.Boc₂O (23.56 g, 108.1 mmol) was added to a suspension of the residue andK₂CO₃ (14.92 g, 108.1 mmol) in 1:1 H₂O/i-PrOH (180 mL) and the resultingsuspension was stirred at 25° C. for 3 h. H₂O was added and theresulting suspension was filtered. The filtrate was extracted withCH₂Cl₂ and the combined extracts were dried over Na₂SO₄. The resultingsolution was concentrated under reduced pressure and flashchromatography (silica gel, hexanes/(1:1 EtOAc/hexanes), 100:0 to 0:100)afforded 7.26 g of viscous oil. NaH (60% dispersion in oil, 1.59 g, 39.8mmol) was added to a solution of the viscous oil in DMF (40 mL) under N₂and the resulting suspension was stirred at 25° C. for 30 min. MeI (1.86mL, 29.8 mmol) was added to the suspension and the resulting suspensionwas stirred at 25° C. for 1 h. H₂O was added and the aqueous solutionwas extracted with CH₂Cl₂. The combined extracts were washed with brineand dried over Na₂SO₄. The resulting solution was concentrated underreduced pressure. Flash chromatography (silica gel, hexanes/(1:1EtOAc/hexanes), 100:0 to 0:100) afforded the title compound (2.71 g,20%) as a white foam: ¹H NMR (300 MHz, CDCl₃) δ 7.38 (br s, 1H),7.34-7.24 (m, 1H), 7.17 (dd, J=8.4, 1.5 Hz, 1H), 3.70-3.57 (m, 7H),3.04-2.91 (m, 4H), 1.48 (s, 9H).

b) 3-(2-Methoxypyridin-4-yl)-6-(trifluoromethyl)pyridazine (CAS RegistryNumber 1173155-65-1) (WO 2009/089482 to Guzzo et al., which is herebyincorporated by reference in its entirety)

3-Chloro-6-(trifluoromethyl)pyridazine (137 mg, 0.751 mmol), 2-methoxy-4-(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (176 mg, 0.749mmol), K₂CO₃ (310 mg, 2.25 mmol) and PdCl₂(dppf) (61 mg, 0.075 mmol)were stirred in DMSO (4 mL). The reaction mixture was degassed, thenback-filled with N₂. The reaction mixture was stirred at 80° C. in apre-heated oil bath for 2 hours. After cooling, the reaction wasquenched with water and extracted with CH₂Cl₂. The organic layer waswashed with H₂O and 5% LiCl, dried with Na₂SO₄, filtered andconcentrated. Flash chromatography (silica gel, hexanes/EtOAc), 100:0 to50:50) afforded the title compound (115 mg, 60%) as a white solid: ¹HNMR (500 MHz, CDCl₃) δ 8.39 (d, J=5.8 Hz, 1H), 8.05 (d, J=8.8 Hz, 1H),7.94 (d, J=8.8 Hz, 1H), 7.62 (dd, J=5.4, 1.5 Hz, 1H), 7.45 (s, 1H), 4.03(s, 3H).

c) 4-(6-(Trifluoromethyl)pyridazin-3-yl)pyridin-2 (1H)-one (CAS RegistryNumber 1173155-66-2) (WO 2009/089482 to Guzzo et al., which is herebyincorporated by reference in its entirety)

3-(2-Methoxypyridin-4-yl)-6-(trifluoromethyl)pyridazine (115 mg, 0.451mmol) was stirred in concentrated hydrochloric acid (20 mL) at 120° C.for 18 h and then concentrated. The residue was adjusted to pH 8 with 6N NaOH and the solids were filtered off, washed with water and driedunder vacuum to provide the title compound (120 mg, quant) as a whitesolid: ¹H NMR (500 MHz, DMSO-d₆) δ 11.87 (s, 1H), 8.61 (d, J=8.9 Hz,1H), 8.42 (d, J=8.9 Hz, 1H), 7.62 (d, J=6.8 Hz, 1H), 7.19 (s, 1H), 7.01(dd, J=6.8, 1.6 Hz, 1H).

d) tert-Butyl6-methyl-8-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate

A suspension of 4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one(106 mg, 0.438 mmol), tert-butyl8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate(183 mg, 0.482 mmol), CuI (100 mg, 0.526 mmol), 8-hydroxyquinoline (13mg, 0.09 mmol) and Cs₂CO₃ (157 mg, 0.482 mmol) in DMSO (10 mL) wasdegassed under reduced pressure for 45 min. The suspension was put underAr and stirred at 135° C. overnight. The suspension was cooled,9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH (10 mL) was added and the resultingsuspension was stirred at 25° C. for 30 min. The suspension was passedthrough a plug of silica gel and the filtrate was washed with brine. Theresulting solution was dried over Na₂SO₄ and concentrated under reducedpressure. Flash chromatography (silica gel, (1:1EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) affordedthe title compound (74 mg, 30%) as a viscous oil: ¹H NMR (300 MHz,CDCl₃) δ 8.10 (d, J=8.7 Hz, 1H), 7.97 (d, J=8.7 Hz, 1H), 7.65 (d, J=6.9Hz, 1H), 7.62-7.53 (m, 1H), 7.33 (br s, 1H), 7.30-7.21 (overlapping withsolvent peak, 2H), 7.08 (d, J=8.1 Hz, 1H), 3.71-3.62 (m, 7H), 3.11-2.98(m, 4H), 1.49 (s, 9H).

e)1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-(6-(trifluormethyl)pyridazin-3-yl)pyridin-2(1H)-onedihydrochloride

TFA (1 ml) was added to a solution of tert-butyl6-methyl-8-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (70 mg, 0.13 mmol) in CH₂Cl₂ (10 mL) underN₂, and the resulting solution was stirred for 1 h at 25° C. SaturatedNaHCO₃ solution was added, and the phases were separated. The aqueousphase was extracted with CH₂Cl₂, and the combined organic extracts weredried over Na₂SO₄. The resulting solution was concentrated under reducedpressure. Flash chromatography (silica gel, (1:1EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded39 mg of a yellow solid. 2 N HCl in Et₂O (0.07 mL, 0.14 mmol) was addedto a solution of the yellow solid in CH₂Cl₂ (10 mL) under N₂, and theresulting solution was stirred at 25° C. for 30 min. The solution wasconcentrated under reduced pressure to afford the title compound (39.5mg, 59%) as a yellow powder: ¹H NMR (500 MHz, DMSO-d₆) δ 9.03 (br s,2H), 8.70 (d, J=9.0 Hz, 1H), 8.46 (d, J=9.0 Hz, 1H), 7.90 (d, J=7.0 Hz,1H), 7.62-7.59 (m, 2H), 7.38 (s, 1H), 7.17 (d, J=6.5 Hz, 1H), 7.08 (d,J=9.0 Hz, 1H), 3.72 (s, 3H), 3.43-3.30 (m, 4H), 3.28-3.25 (m, 2H),3.17-3.11 (m, 2H); ESI MS m/z 440 [M+H]⁺.

Example 3 Preparation of1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-onedihydrochloride

a) 2′-Methoxy-5-(trifluoromethyl)-2,4′-bipyridine (CAS Registry Number1108184-24-2) (WO 2009/015037 to Guzzo et al., which is herebyincorporated by reference in its entirety)

2-Bromo-5-trifluoromethylpyridine (410 mg, 2.13 mmol) and2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (500mg, 1.81 mmol) were reacted according to Example 2 (step b) to providethe title compound (337 mg, 62%) as a white solid: ¹H NMR (300 MHz,CDCl₃) δ 8.96 (s, 1H), 8.31 (d, J=5.4 Hz, 1H), 8.04 (dd, J=8.3, 2.1 Hz,1H), 7.87 (d, J=8.3 Hz, 1H), 7.51 (dd, J=5.4, 1.4 Hz, 1H), 7.36 (s, 1H),3.52 (s, 3H).

b) 4-(5-(Trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (CAS RegistryNumber 1108184-25-3) (WO 2009/015037 to Guzzo et al., which is herebyincorporated by reference in its entirety)

2′-Methoxy-5-(trifluoromethyl)-2,4′-bipyridine (337 mg, 1.32 mmol) wasreacted reacted according to Example 2 (step c) to provide the titlecompound (289 mg, 89%) as a white solid: ¹H NMR (300 MHz, DMSO-d₆) δ11.08 (s, 1H) 9.10 (s, 1H), 8.35 (dd, J=8.4, 2.1 Hz, 1H), 8.25 (d, J=8.3Hz, 1H), 7.53 (d, J=6.8, 1H), 7.09 (d, J=1.3 Hz, 1H), 6.90 (dd, J=6.8,1.6 Hz, 1H).

c) tert-Butyl6-methyl-8-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate

A suspension of 4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one(178 mg, 0.740 mmol), tert-butyl8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate(255 mg, 0.673 mmol), CuI (154 mg, 0.808 mmol), 8-hydroxyquinoline (20mg, 0.14 mmol) and Cs₂CO₃ (241 mg, 0.740 mmol) in DMSO (10 mL) wasdegassed under reduced pressure for 45 min. The suspension was put underAr and stirred at 135° C. for 36 h. The suspension was cooled, 9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH was added and the resulting suspension was stirred at25° C. for 20 min. The suspension was passed through a plug of silicagel, and the filtrate was washed with brine. The resulting solution wasdried over Na₂SO₄ and concentrated under reduced pressure. Flashchromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded the title compound (133 mg,33%) as a yellow solid: ¹H NMR (300 MHz, CDCl₃) δ 9.00 (br s, 1H), 8.07(br d, J=8.3 Hz, 1H), 7.91 (d, J=8.3 Hz, 1H), 7.60-7.52 (m, 2H), 7.32(s, 1H), 7.28-7.20 (overlapping with solvent peak, 1H), 7.11-7.02 (m,2H), 3.84-3.60 (m, 7H), 3.12-2.95 (m, 4H), 1.49 (s, 9H).

d)1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-onedihydrochloride

TFA (1 ml) was added to a solution of tert-butyl6-methyl-8-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate(133 mg, 0.247 mmol) in CH₂Cl₂ (10 mL) under N₂, and the resultingsolution was stirred for 1 h at 25° C. Saturated NaHCO₃ solution wasadded, and the phases were separated. The aqueous phase was extractedwith CH₂Cl₂, and the combined organic extracts were dried over Na₂SO₄.The resulting solution was concentrated under reduced pressure. Flashchromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded 39 mg of a yellow solid.Preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H₂Owith 0.05% TFA and CH₃CN with 0.05% TFA) afforded 10 mg of a yellowsolid. 2 N HCl in Et₂O (0.02 mL, 0.04 mmol) was added to a solution ofthe yellow solid in CH₂Cl₂ (10 mL) under N₂, and the resulting solutionwas stirred at 25° C. for 30 min. The solution was concentrated underreduced pressure to afford the title compound (12 mg, 9%) as a yellowpowder: mp 310-312° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.15 (s, 1H), 9.00(br s, 2H), 8.40 (d, J=8.5 Hz, 1H), 8.34 (d, J=8.5 Hz, 1H), 7.83 (d,J=7.0 Hz, 1H), 7.61-7.56 (m, 2H), 7.28 (d, J=2.0 Hz, 1H), 7.08-7.05 (m,2H), 3.72 (s, 3H), 3.43-3.23 (m, 6H), 3.16-3.11 (m, 2H); ESI MS m/z 439[M+H]⁺.

Example 4 Preparation of1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-onedihydrochloride

a) 2′-Methoxy-6-(trifluoromethyl)-3,4′-bipyridine (CAS Registry Number1173155-80-0) (WO 2009/089482 to Guzzo et al., which is herebyincorporated by reference in its entirety)

2-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.24g, 0.53 mmol) and 5-bromo-2-(trifluoromethyl)pyridine (2.4 g, 11 mmol)were reacted according to the procedure of Example 2 (step b) to providethe title compound (1.1 g, 81%) as a white solid: ESI MS m/z 255 [M+H].

b) 4-(6-(Trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one (CAS RegistryNumber 1173155-81-1) (WO 2009/089482 to Guzzo et al., which is herebyincorporated by reference in its entirety)

2′-Methoxy-6-(trifluoromethyl)-3,4′-bipyridine (1.1 g, 4.3 mmol) wasreacted according to the procedure of Example 2 (step c) to provide thetitle compound (522 mg, 50%) as a white solid: ¹H NMR (500 MHz, DMSO-d₆)δ 11.8 (br s, 1H), 9.10 (s, 1H), 8.40 (dd, J=8.1, 1.2 Hz, 1H), 8.00 (d,J=8.2 Hz, 1H), 7.56 (d, J=6.7 Hz, 1H), 6.81 (s, 1H), 6.63 (dd, J=6.7,1.3 Hz, 1H).

c)1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-onedihydrochloride

A suspension of 4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one (67mg, 0.28 mmol), tert-butyl8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate(116 mg, 0.307 mmol), CuI (64 mg, 0.34 mmol), 8-hydroxyquinoline (8 mg,0.06 mmol) and Cs₂CO₃ (100 mg, 0.307 mmol) in DMSO (10 mL) was degassedunder reduced pressure for 45 min. The suspension was put under N₂ andstirred at 135° C. for 24 h. The suspension was cooled, 9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH was added, and the resulting suspension was stirred at25° C. for 20 min. The suspension was passed through a plug of silicagel, and the filtrate was washed with brine. The resulting solution wasdried over Na₂SO₄ and concentrated under reduced pressure. Flashchromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded 101 mg of a yellow solid.Preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H₂Owith 0.05% TFA and CH₃CN with 0.05% TFA) afforded 70 mg of a viscousoil. 2 N HCl in Et₂O (100 mL) was added to a solution of the viscous oilin 1:1 CH₂Cl₂/MeOH (2 mL) under N₂ and the resulting suspension wasstirred at 25° C. for 19 h. The suspension was filtered, and the solidwas washed with CH₂Cl₂. The solid was washed with 9:1 CH₂Cl₂/MeOH andthe resulting 9:1 CH₂Cl₂/MeOH solution was concentrated under reducedpressure to afford the title compound (35 mg, 25%) as a yellow solid: ¹HNMR (500 MHz, DMSO-d₆) 6 9.20 (d, J=1.5 Hz, 1H), 9.15-9.02 (m, 2H), 8.49(dd, J=8.0, 2.0 Hz, 1H), 8.06 (d, J=8.5 Hz, 1H), 7.84 (d, J=7.3 Hz, 1H),7.60-7.53 (m, 2H), 7.06 (dd, J=8.5, 1.5 Hz, 1H), 7.00 (d, J=2.0 Hz, 1H),6.80 (dd, J=7.3, 2.0 Hz, 1H), 3.72 (s, 3H), 3.42-3.37 (m, 2H), 3.36-3.24(m, 4H), 3.16-3.12 (m, 2H); ESI MS m/z 439 [M+H]⁺.

Example 5 Preparation of1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-onedihydrochloride

a) 2-Methoxy-4((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridine (CASRegistry Number 1173155-95-7) (WO 2009/089482 to Guzzo et al., which ishereby incorporated by reference in its entirety)

4-Bromo-2-methoxypyridine (3.06 g, 16.2 mmol),(6-(trifluoromethyl)pyridin-3-yl)methanol (2.74 g, 15.5 mmol),3,4,7,8-tetramethylphenanthroline (0.36 g, 0.15 mmol), CuI (0.14 g, 0.74mmol) and Cs₂CO₃ (7.57 g, 23.2 mmol) were combined in toluene (15 mL)and heated to reflux under a nitrogen atmosphere for 16 h. Upon coolingthe mixture was purified by flash column chromagraphy (silica gel,hexanes/EtOAc, 1:0 to 1:1) to provide the title compound (3.19 g, 72%)as a red oil: ¹H NMR (300 MHz, CDCl₃) δ 8.78 (s, 1H), 8.02 (d, J=5.9 Hz,1H), 7.95 (d, J=8.1 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 6.55 (dd, J=5.9,2.2 Hz, 1H), 6.26 (d, J=2.2 Hz, 1H), 5.16 (s, 2H), 3.93 (s, 3H).

b) 4((6-(Trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-one (CASRegistry Number 1173155-96-8) (WO 2009/089482 to Guzzo et al., which ishereby incorporated by reference in its entirety)

2-Methoxy-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridine (3.19 g,11.2 mmol) was reacted according to the procedure of Example 2 (step c)to provide the title compound (2.04 g, 67%) as a white solid: ¹H NMR(300 MHz, DMSO-d₆) δ 11.2 (br s, 1H), 8.84 (s, 1H), 8.14 (d, J=8.5 Hz,1H), 7.96 (d, J=8.0 Hz, 1H), 7.28 (d, J=7.3 Hz, 1H), 5.95 (dd, J=7.3,2.5 Hz, 1H), 5.82 (d, J=2.4 Hz, 1H), 5.25 (s, 2H).

c)1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-onedihydrochloride

A suspension of4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-one (147 mg,0.544 mmol), tert-butyl8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate(226 mg, 0.598 mmol), CuI (124 mg, 0.653 mmol), 8-hydroxyquinoline (16mg, 0.11 mmol) and Cs₂CO₃ (195 mg, 0.598 mmol) in DMSO (10 mL) wasdegassed under reduced pressure for 45 min. The suspension was put underN₂ and stirred at 135° C. overnight. The suspension was cooled,9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH was added, and the resulting suspension wasstirred at 25° C. for 30 min. The suspension was passed through a plugof silica gel, and the filtrate was washed with brine. The resultingsolution was dried over Na₂SO₄ and concentrated under reduced pressure.Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded a brown solid. PreparativeHPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H₂O with 0.05%TFA and CH₃CN with 0.05% TFA) afforded 95 mg of a yellow powder. 2 N HClin Et₂O (200 mL) was added to a solution of the yellow powder in 1:1CH₂Cl₂/MeOH (4 mL) under N₂ and the resulting suspension was stirred at25° C. for 18 h. The suspension was filtered and the solid was washedwith Et₂O to afford the title compound (80 mg, 27%) as a yellow solid:mp 296-300° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.20 (br s, 2H), 8.89 (s,1H), 8.19 (d, J=8.3 Hz, 1H), 8.00 (d, J=8.3 Hz, 1H), 7.58 (d, J=7.5 Hz,1H), 7.52 (d, J=8.0 Hz, 1H), 7.44 (s, 1H), 6.95 (d, (d, J=8.0 Hz, 1H),6.14 (d, J=7.5 Hz, 1H), 6.01 (s, 1H), 5.35 (s, 2H), 3.69 (s, 3H),3.41-3.29 (m, 4H), 3.28-3.22 (m, 2H), 3.14-3.10 (m, 2H); ESI MS m/z 469[M+H]⁺.

Example 6 Preparation of1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2(1H)-onedihydrochloride

a) 5-(2-Methoxypyridin-4-yl)-2-(trifluoromethyl)pyrimidine (CAS RegistryNumber 1173155-89-9) (WO 2009/089482 to Guzzo et al., which is herebyincorporated by reference in its entirety)

2-Methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.0g, 8.5 mmol) and 5-chloro-2-(trifluoromethyl)pyrimidine (2.3 g, 13 mmol)were reacted according to the procedure of Example 2 (step b) to providethe title compound (1.0 g, 46%) as a white solid: ¹H NMR (300 MHz,CDCl₃) δ 9.10 (s, 2H), 8.35 (d, J=5.5 Hz, 1H), 7.11 (dd, J=5.5, 1.6 Hz,1H), 6.98 (d, J=1.6 Hz, 1H), 4.02 (s, 3H).

b) 4-(2-(Trifluoromethyl)pyrimidin-5-yl)pyridin-2(111)-one (CAS RegistryNumber 1173155-90-2) (WO 2009/089482 to Guzzo et al., which is herebyincorporated by reference in its entirety)

5-(2-Methoxypyridin-4-yl)-2-(trifluoromethyl)pyrimidine (900 mg, 3.5mmol) was reacted according to the procedure of Example 2 (step c) toprovide the title compound (470 mg, 56%) as an orange solid: ¹H NMR (300MHz, DMSO-d₆) δ 11.6 (br s, 1H), 9.41 (s, 2H), 7.61 (d, J=6.8 Hz, 1H),6.91 (s, 1H), 6.68 (dd, J=6.8, 1H).

c)1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2(1H)-onedihydrochloride

A suspension of 4-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2(1H)-one(95 mg, 0.39 mmol), tert-butyl8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate(124 mg, 0.327 mmol), CuI (75 mg, 0.39 mmol), 8-hydroxyquinoline (9 mg,0.07 mmol) and Cs₂CO₃ (117 mg, 0.360 mmol) in DMSO (10 mL) was degassedunder reduced pressure for 45 min. The suspension was put under N₂ andstirred at 135° C. overnight. The suspension was cooled, 9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH (10mL) was added, and the resulting suspension wasstirred at 25° C. for 30 min. The suspension was passed through a plugof silica gel and the filtrate was washed with brine. The resultingsolution was dried over Na₂SO₄ and concentrated under reduced pressure.Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded a green solid. PreparativeHPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H₂O with 0.05%TFA and CH₃CN with 0.05% TFA) afforded 40 mg of a yellow powder. 2 N HClin Et₂O (100 mL) was added to a solution of the yellow powder in 1:1CH₂Cl₂/MeOH (10 mL) under N₂, and the resulting suspension was stirredat 25° C. for 18 h. The suspension was filtered, and the solid waswashed with Et₂O to afford the title compound (32 mg, 16%) as a yellowsolid: ¹H NMR (500 MHz, DMSO-d₆) δ 9.51 (s, 2H), 9.10 (br s, 2H), 7.89(d, J=7.0 Hz, 1H), 7.62-7.56 (m, 2H), 7.12 (s, 1H), 7.05 (d, J=8.5 Hz,1H), 6.86 (d, J=7.0 Hz, 1H), 3.72 (s, 3H), 3.42-3.33 (m, 4H), 3.29-3.24(m, 2H), 3.16-3.12 (m, 2H); ESI MS m/z 440 [M+H]⁺.

Example 7 Preparation of4-(Benzyloxy)-1-(1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-onehydrochloride a) tert-Butyl8-bromo-6-tosyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate

A solution of 3-bromophenylhydrazine hydrochloride (10.39 g, 46.38 mmol)and tert-butyl 4-oxoazepane-l-carboxylate (9.927 g, 46.38 mmol) in 15:2EtOH/(concentrated HCl solution) (68 mL) was stirred at reflux for 18 h.The solution was concentrated under reduced pressure to afford aresidue. Boc₂O (30.33 g, 139.1 mmol) was added to a suspension of theresidue and K₂CO₃ (19.20 g, 139.1 mmol) in 1:1 H₂O/i-PrOH (180 mL), andthe resulting suspension was stirred at 25° C. for 1.5 h. H₂O was addedand the resulting suspension was filtered. The filtrate was extractedwith CH₂Cl₂, and the combined extracts were dried over Na₂SO₄. Theresulting solution was concentrated under reduced pressure, and flashchromatography (silica gel, hexanes/(1:1 EtOAc/hexanes), 100:0 to 0:100)afforded 6.73 g of an amorphous solid. TsCl (4.21 g, 22.1 mmol) wasadded to a biphasic system of the amorphous solid and (Bu₄NH)₂SO₄ (50%weight solution in H₂O, 1.5 mL) in 5:3 toluene/(6 N NaOH in H₂O ) (240mL), and the resulting biphasic system was stirred at 25° C. for 1 h.The phases were separated. The organic phase was washed with H₂O, driedover Na₂SO₄ and concentrated under reduced pressure. Flashchromatography (silica gel, hexanes/(1:1 EtOAc/hexanes), 100:0 to 0:100)afforded the title compound (3.78 g, 16%) as a yellow foam: ¹H NMR (300MHz, CDCl₃) δ 8.45-8.39 (m, 1H), 7.63-7.54 (m, 2H), 7.37 (dd, J=8.4, 1.8Hz, 1H), 7.30-7.18 (m, 3H), 3.69-3.51 (m, 4H), 3.35-3.27 (m, 2H),2.90-2.79 (m, 2H), 2.37 (s, 3H), 1.45 (s, 9H).

b)4-(Benzyloxy)-1-(1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-onehydrochloride

A suspension of 4-(benzyloxy)pyridin-2(1H)-one (71 mg, 0.35 mmol),tert-butyl8-bromo-6-tosyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate(202 mg, 0.389 mmol), CuI (81 mg, 0.43 mmol), 8-hydroxyquinoline (62 mg,0.43 mmol) and Cs₂CO₃ (127 mg, 0.389 mmol) in DMSO (10 mL) was degassedunder reduced pressure for 45 min. The suspension was put under N₂ andstirred at 135° C. for 4.5 h. The suspension was cooled, 9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension wasstirred at 25° C. for 30 min. The suspension was passed through a plugof silica gel, and the filtrate was washed with brine. The resultingsolution was dried over Na₂SO₄ and concentrated under reduced pressure.Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded 190 mg of a yellow solid.NaOH (594 mg, 14.8 mmol) was added to a solution of the yellow solid in1:1 MeOH/CH₂Cl₂ (20 mL) under N₂, and the resulting suspension wasstirred at reflux for 16 h. The reaction was cooled, H₂O was added, andthe resulting suspension was filtered. Flash chromatography (silica gel,(1:1 EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100)afforded a green solid. Preparative HPLC (Phenomenex Luna C18 (2),250.0×50.0 mm, 10 micron, H₂O with 0.05% TFA and CH₃CN with 0.05% TFA)afforded 50 mg of a white powder. 2 N HCl in Et₂O (200 mL) was added toa solution of the white powder in 1:1 CH₂Cl₂/MeOH (4 mL) under N₂, andthe resulting suspension was stirred at 25° C. for 18 h. The suspensionwas filtered, and the solid was washed with Et₂O to afford the titlecompound (35 mg, 23%) as a white solid: mp 258-260° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 11.18 (s, 1H), 9.06 (br s, 2H), 7.57-7.35 (m, 7H), 7.25 (s,1H), 6.90 (d, J=8.0 Hz), 6.11-6.07 (m, 1H), 5.96 (s, 1H), 5.15 (s, 2H),3.45-3.30 (m, 4H), 3.20-3.15 (m, 2H), 3.12-3.06 (m, 2H); ESI MS m/z 386[M+H]⁺.

Example 8 Preparation of1-(1,2,3,4,5,6-Hexahydroazepino[4,5-b]indol-8-yl)-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-onedihydrochloride a) tert-Butyl8-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-6-tosyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate

A suspension of 4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one(78 mg, 0.32 mmol), tert-butyl8-bromo-6-tosyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (183 mg, 0.353 mmol), CuI (73 mg, 0.39mmol), 8-hydroxyquinoline (9 mg, 0.06 mmol) and Cs₂CO₃ (115 mg, 0.353mmol) in DMSO (10 mL) was degassed under reduced pressure for 45 min.The suspension was put under N₂ and stirred at 135° C. overnight. Thesuspension was cooled, 9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH (10 mL) was added,and the resulting suspension was stirred at 25° C. for 30 min. Thesuspension was passed through a plug of silica gel, and the filtrate waswashed with brine. The resulting solution was dried over Na₂SO₄ andconcentrated under reduced pressure. Flash chromatography (silica gel,(1:1 EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100)afforded the title compound (95 mg, 44%) as a yellow viscous oil: ¹H NMR(300 MHz, CDCl₃) δ 8.35 (br s, 1H), 8.12 (d, J=8.9 Hz, 1H), 7.99 (d,J=8.9 Hz, 1H), 7.71-7.63 (m, 4H), 7.54-7.47 (m, 1H), 7.39-7.22 (m, 4H),3.73-3,58 (m, 4H), 3.44-3.31 (m, 2H), 2.95-2.86 (m, 2H), 2.37 (s, 3H),1.47 (s, 9H).

b)1-(1,2,3,4,5,6-Hexahydroazepino[4,5-b]indol-8-yl)-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one dihydrochloride

NaOH (293 mg, 7.33 mmol) was added to a solution of tert-butyl8-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-6-tosyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate(100 mg, 0.147 mmol) in 1:1 MeOH/CH₂Cl₂ (20 mL) under N₂ and theresulting suspension was stirred at reflux for 19 h. The reaction wascooled, H₂O was added, and the resulting suspension was filtered. Flashchromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded 35 mg of a yellow solid. 2N HCl in Et₂O (200 mL) was added to a solution of the white powder in1:1 CH₂Cl₂/MeOH (4 mL) under N₂, and the resulting suspension wasstirred at 25° C. for 18 h. The suspension was filtered, and the solidwas washed with Et₂O to afford the title compound (18.6 mg, 25%) as ayellow solid: ¹H NMR (500 MHz, DMSO-d₆) δ 11.27 (s, 1H), 9.09 (br s,2H), 8.69 (d, J=9.0 Hz, 1H), 8.46 (d, J=9.0 Hz, 1H), 7.89 (d, J=7.3 Hz,1H), 7.56 (d, J=8.5 Hz, 1H), 7.40 (s, 1H), 7.36 (s, 1H), 7.16 (d, J=7.3Hz, 1H), 7.04 (d, J=8.5 Hz, 1H), 3.41-3.25 (m, 4H), 3.23-3.17 (m, 2H),3.14-3.09 (m, 2H); ESI MS m/z 426 [M+H]⁻.

Example 9 Preparation of1-(1,2,3,4,5,6-Hexahydroazepino[4,5-b]indol-8-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-onedihydrochloride

A suspension of 4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one(109 mg, 0.454 mmol), tert-butyl8-bromo-6-tosyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate(259 mg, 0.500 mmol), CuI (104 mg, 0.545 mmol), 8-hydroxyquinoline (13mg, 0.09 mmol) and Cs₂CO₃ (163 mg, 0.500 mmol) in DMSO (10 mL) wasdegassed under reduced pressure for 45 min. The suspension was put underN₂ and stirred at 135° C. for 15 h. The suspension was cooled, 9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension wasstirred at 25° C. for 30 min. The suspension was passed through a plugof silica gel, and the filtrate was washed with brine. The resultingsolution was dried over Na₂SO₄ and concentrated under reduced pressure.Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded 120 mg of a yellow solid.NaOH (353 mg, 8.82 mmol) was added to a solution of the yellow solid in1:1 MeOH/CH₂Cl₂ (20 mL) under N₂, and the resulting suspension wasstirred at reflux for 16 h. The reaction was cooled, H₂O was added, andthe phases were separated. The organic phase was extracted with CH₂Cl₂.The combined extracts were dried over Na₂SO₄ and concentrated underreduced pressure. Flash chromatography (silica gel, (1:1EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded91 mg of a yellow solid. 2 N HCl in Et₂O (100 mL) was added to asolution of the yellow solid in 1:1 CH₂Cl₂/MeOH (10 mL) under N₂, andthe resulting suspension was stirred at 25° C. for 18 h. The suspensionwas filtered, and the solid was washed with Et₂O and CH₂Cl₂ to affordthe title compound (75 mg, 33%) as a orange solid: mp 288-290° C.; ¹HNMR (500 MHz, DMSO-d₆) δ 11.26 (br s, 1H), 9.15 (br s, 1H), 9.08-9.00(m, 2H), 8.40-8.32 (m, 2H), 7.81 (d, J=7.2 Hz, 1H), 7.55 (d, J=8.4 Hz,1H), 7.38 (d, J=1.5 Hz, 1H), 7.27 (d, J=1.8 Hz, 1H), 7.08-7.01 (m, 2H),3.41-3.29 (m, 4H), 3.21-3.14 (m, 2H), 3.13-3.07 (m, 2H); ESI MS m/z 425[M+H]⁺.

Example 10 Preparation of5-((5-Fluoropyridin-2-yl)methoxy)-2-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridazin-3(2H)-onedihydrochloride

a) 5-Hydroxy-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (CASRegistry Number 1008517-74-5) (WO 2008/022979 to Stenkamp et al., whichis hereby incorporated by reference in its entirety)

This compound was prepared in accordance with the procedure of Stenkamp,et al., WO 2008022979, which is hereby incorporated by reference in itsentirety.

b)5-((5-Fluoropyridin-2-yl)methoxy)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one(CAS Registry Number 1008518-11-3) (WO 2008/022979 to Stenkamp et al.,which is hereby incorporated by reference in its entirety)

5-Hydroxy-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (2.62 g, 13.4mmol), 2-(bromomethyl)-5-fluoropyridine (7.6 g, 40 mmol) and K₂CO₃ (9.2g, 67 mmol) were stirred in DMF (40 ml) and CH₂Cl₂ (40 ml) for 48 h. Themixture was diluted with CH₂Cl₂, was washed with 5% LiCl solution (4×)and concentrated. The residue was purified by column chromatography (40g ISCO column column eluting with methylene chloride and a 10:1methanol/ammonium hydroxide mixture; gradient 100% methylene chloride to95% methylene chloride) to yield the title compound (1.1 g, 27%) as alight brown solid: ¹H NMR (300 MHz, CDCl₃) δ 8.47 (s, 1H), 7.73 (d,J=2.9 Hz, 1H), 7.47-7.43 (m, 2H), 6.19 (d, J=2.9 Hz, 1H), 6.03-5.98 (dd,J=10.7, 2.0 Hz, 1H), 5.12 (s, 2H), 4.18-4.08 (m, 1H), 3.78-3.69 (td,J=11.6, 2.6 Hz, 1H), 2.21-2.00 (m, 2H), 1.75-1.60 (m, 4H).

c) 5-((5-Fluoropyridin-2-yl)methoxy)pyridazin-3(2H)-one (CAS RegistryNumber 1008518-42-4) (WO 2008/022979 to Stenkamp et al., which is herebyincorporated by reference in its entirety)

5-((5-Fluoropyridin-2-yl)methoxy)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one(1.1 g, 3.6 mmol) was stirred in MeOH (5 mL), and 2 N HCl in Et₂O (20mL) was added. After 16 h, the mixture was diluted with Et₂O (100 mL)and the solid filtered off. The solid was stirred in NaHCO₃ solution (15mL) for 15 minutes and then refiltered to provide the title compound(620 mg, 78%) as a pink solid: ¹H NMR (300 MHz, DMSO-d₆) δ 12.69 (s,1H), 8.60 (d, J=2.8 Hz, 1H), 7.85-7.78 (td, J=8.7, 2.9 Hz, 1H), 7.76 (d,J=2.7 Hz, 1H), 7.67-7.63 (dd, J=8.6, 4.5 Hz, 1H), 6.31 (s, 1H), 5.25 (s,2H).

d)5-((5-Fluoropyridin-2-yl)methoxy)-2-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridazin-3(2H)-onedihydrochloride

A suspension of 5-((5-fluoropyridin-2-yl)methoxy)pyridazin-3(2H)-one(110 mg, 0.500 mmol), tert-butyl8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate(208 mg, 0.550 mmol), CuI (209 mg, 1.10 mmol), 8-hydroxyquinoline (15mg, 0.100 mmol) and Cs₂CO₃ (179 mg, 0.550 mmol) in DMSO (10 mL) wasdegassed under reduced pressure for 45 min. The suspension was put underN₂ and stirred at 135° C. overnight. The suspension was cooled anddiluted with CH₂Cl₂. The resulting solution was washed with brine, driedover Na₂SO₄ and concentrated under reduced pressure. Flashchromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded a white solid. The solidwas triturated with MeOH and dried under reduced pressure to afford awhite solid. 2 N HCl in Et₂O (200 mL) was added to a solution of thewhite solid in 1:1 CH₂Cl₂/MeOH (5 mL) under N₂, and the resultingsuspension was stirred at 25° C. for 18 h. The suspension was filtered,and the solid was washed with Et₂O to afford the title compound (22 mg,9%) as a white solid: mp 250-254° C.; ¹H NMR (500 MHz, DMSO-d₆) δ9.10-8.92 (m, 2H), 8.64 (d, J=2.5 Hz, 1H), 7.99 (d, J=3.0 Hz, 1H), 7.85(ddd, J=8.5, 8.5, 3.0 Hz, 1H), 7.71 (dd, J=8.5, 4.0 Hz, 1H), 7.55-7.51(m, 2H), 7.08 (dd, J=8.0, 2.0 Hz, 1H), 6.52 (d, J=2.5 Hz, 1H), 5.29 (s,2H), 3.69 (s, 3H), 3.42-3.32 (m, 4H), 3.27-3.22 (m, 2H), 3.14-3.10 (m,2H); ESI MS m/z 420 [M+H]⁺.

Example 11 Preparation of1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-(6-methylpyridin-3-yl)pyridin-2(1H)-onedihydrochloride

a) 2′-Methoxy-6-methyl-3,4′-bipyridine (CAS Registry Number1173156-60-9) (WO 2009/089482 to Guzzo et al., which is herebyincorporated by reference in its entirety)

2-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (3.5 g,16 mmol) and 4-bromo-2-methoxypyridine (2.0 g, 11 mmol) were reactedaccording to Example 2 (step b) to provide the title compound (2.1 g,98%) as a brown solid: ¹H NMR (300 MHz, CDCl₃) δ 8.75 (d, J=2.1 Hz, 1H),8.23 (d, J=5.4 Hz, 1H), 7.78 (dd, J=8.0, 2.4 Hz, 1H), 7.24 (d, J=8.1,1H), 7.08 (dd, J=5.4, 1.5 Hz, 1H), 6.84 (d, J=1.0, 1H), 3.98 (s, 3H),2.61 (s, 3H).

b) 4-(6-Methylpyridin-3-yl)pyridin-2(1H)-one (CAS Registry Number1173156-63-2) (WO 2009/089482 to Guzzo et al., which is herebyincorporated by reference in its entirety)

2′-Methoxy-6-methyl-3,4′-bipyridine (2.1 g, 10.4 mmol) was reactedaccording to Example 2 (step c) to provide the title compound (1.36 mg,68%) as a white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 11.65 (s, 1H) 8.78(d, J=2.1 Hz, 1H), 8.01 (dd, J=8.1, 2.5 Hz, 1H), 7.47 (d, J=6.9 Hz, 1H),7.36 (d, J=8.1, 1H), 6.66 (d, J=1.4 Hz, 1H), 6.55 (dd, J=6.9, 1.8 Hz,1H), 2.51 (s, 3H).

c)1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-(6-methylpyridin-3-yl)pyridin-2(1H)-onedihydrochloride

A suspension of 4-(6-methylpyridin-3-yl)pyridin-2(1H)-one (96 mg, 0.52mmol), tert-butyl8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate(235 mg, 0.619 mmol), CuI (118 mg, 0.619 mmol), 8-hydroxyquinoline (15mg, 0.10 mmol) and Cs₂CO₃ (185 mg, 0.568 mmol) in DMSO (10 mL) wasdegassed under reduced pressure for 45 min. The suspension was put underN₂, and stirred at 135° C. overnight. The suspension was cooled,9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resultingsuspension was stirred at 25° C. for 24 h. The suspension was passedthrough a plug of silica gel, and activated carbon was added to thefiltrate. The suspension was filtered through Celite, and the filtratewas washed with brine. The resulting solution was dried over Na₂SO₄ andconcentrated under reduced pressure. Flash chromatography (silica gel,(1:1 EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100)afforded an off-white solid. 1.25 N HCl in MeOH (5 mL) was added to theoff-white solid under N₂, and the resulting suspension was stirred at25° C. for 20 h. The suspension was concentrated under reduced pressureto afford the title compound (118 mg, 50%) as a yellow solid: ¹H NMR(500 MHz, DMSO-d₆) δ 9.27 (br s, 2H), 9.03 (s, 1H), 8.47-8.40 (m, 1H),7.81 (d, J=7.0 Hz, 1H), 7.71-7.64 (m, 1H), 7.57 (d, J=8.5 Hz, 1H), 7.53(d, J=1.5 Hz, 1H), 7.04 (dd, J=8.5, 2.0 Hz, 1H), 6.95 (br s, 1H), 6.78(dd, J=7.0, 2.0 Hz, 1H), 3.71 (s, 3H), 3.41-3.31 (m, 4H), 3.29-3.25 (m,2H), 3.17-3.12 (m, 2H), 2.66 (s, 3H); ESI MS m/z 385 [M+H]⁺.

Example 12 Preparation of1-(1,2,3,4,5,6-Hexahydroazepino[4,5-b]indol-8-yl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-onehydrochloride a) Di-tert-butyl8-bromo-1,2,4,5-tetrahydroazepino[4,5-b]indole-3,6-dicarboxylate

A solution of 3-bromophenylhydrazine hydrochloride (15.75 g, 70.33 mmol)and tert-butyl 4-oxoazepane-1-carboxylate (15.05 g, 70.33 mmol) in 15:2EtOH/(12 N HCl solution) (102 mL) was stirred at reflux overnight. Thesolution was concentrated under reduced pressure to afford a red oil.Boc₂O (46.00 g, 211.0 mmol) was added to a suspension of the red oil andK₂CO₃ (29.12 g, 211.0 mmol) in 1:1 H₂O/i-PrOH (180 mL), and theresulting suspension was stirred at 25° C. for 2 h. H₂O was added, andthe resulting suspension was filtered. The filtrate was extracted withCH₂Cl₂, and the combined extracts were dried over Na₂SO₄. The resultingsolution was concentrated under reduced pressure, and flashchromatography (silica gel, hexanes/(1:1 EtOAc/hexanes), 100:0 to 0:100)afforded a viscous red oil. NaH (60% dispersion in oil, 5.626 g, 140.7mmol) was added to a solution of the viscous red oil in DMF (60 mL)under N₂, and the resulting suspension was stirred at 25° C. for 45 min.MeI (6.6 mL, 106 mmol) was added to the suspension, and the resultingsuspension was stirred at 25° C. for 2 h. H₂O was added, and the aqueoussolution was extracted with CH₂Cl₂. The combined extracts were washedwith brine, dried over Na₂SO₄ and concentrated under reduced pressure.Flash chromatography (silica gel, hexanes/(1:1 EtOAc/hexanes), 100:0 to0:100) afforded tert-butyl8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate(1.62 g, 6%) as a yellow foam and the title compound (2.80 g, 9%) as awhite foam: ¹H NMR (300 MHz, CDCl₃) δ 8.28 (br s, 0.5H), 8.21 (br s,0.5H), 7.34 (dd, J=8.4, 1.5 Hz, 1H), 7.30-7.22 (1H, overlapping withsolvent), 3.85-3.63 (m, 4H), 3.39-3.32 (m, 2H), 2.99-2.91 (m, 2H), 1.68(s, 4.5H), 1.67 (s, 4.5H), 1.48 (s, 9H).

b) 4-(4-(Trifluoromethyl)phenyl)pyridine 1-oxide (CAS Registry Number545396-52-9) (WO 2003/049702 to Bo et al., which is hereby incorporatedby reference in its entirety)

4-Chloropyridine-N-oxide (3.0 g, 23 mmol),4-trifluoromethylphenylboronic acid (6.57 g, 34.6 mmol), K₂CO₃ (4.8 g,35 mmol) and PdCl₂(dppf) (470 mg, 0.57 mmol) were stirred in DMSO (40mL) under vacuum for 30 min. The flask was flushed with nitrogen, andthe mixture was heated to 80° C. for 10 min. Upon cooling, the mixturewas diluted with methylene chloride and washed with 5% lithium chloridesolution (5×), dried, concentrated, and the residue was purified byflash column chromatography (40 g ISCO column eluting with methylenechloride and a methanol/ammonia mixture (10:1); gradient 100% methylenechloride to 80% methylene chloride over 30 min at 40 mL/min) to providethe title compound (1.90 g, 34%) as a tan solid: ESI MS m/z 240 [M+H]⁺.

c) 4-(4-(Trifluoromethyl)phenyl)pyridin-2(1H)-one (CAS Registry Number942947-10-6) (U.S. Published Patent Application No. 2007/149513 to Chenet al., which is hereby incorporated by reference in its entirety)

4-(4-(Trifluoromethyl)phenyl)pyridine-1-oxide (1.9 g, 7.9 mmol) washeated to 140° C. in acetic anhydride (80 mL) for 5 h. The mixture wasconcentrated and then heated at 80° C. for 1 h in a mixture of MeOH (20mL) and aqueous 1 N NaOH (l5 mL). The resulting black solution wasconcentrated to a volume of 15 mL, and the solid was filtered off,rinsed with CH₂Cl₂ and dried under vacuum to provide the title compound(1.26 g, 66%) as a brown solid: ¹H NMR (300 MHz, CD₃OD) δ 7.80-7.74 (brm, 5H), 6.85-6.66 (br m, 2H).

d)1-(1,2,3,4,5,6-Hexahydroazepino[4,5-b]indol-8-yl)-4-(4-(trifluoro-methyl)phenyl)pyridin-2(1H)-onehydrochloride

A suspension of 4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one (219 mg,0.915 mmol), di-tert-butyl8-bromo-1,2,4,5-tetrahydroazepino[4,5-b]indole-3,6-dicarboxylate (467mg, 1.01 mmol), CuI (261 mg, 1.37 mmol), 8-hydroxyquinoline (27 mg, 0.18mmol) and Cs₂CO₃ (329 mg, 1.01 mmol) in DMSO (10 mL) was degassed underreduced pressure for 45 min. The suspension was put under N₂ and stirredat 135° C. overnight. The suspension was cooled, 9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH was added, and the resulting suspension was stirred at25° C. for 30 min. The suspension was passed through a plug of silicagel, and the filtrate was washed with brine. The resulting solution wasdried over Na₂SO₄ and concentrated under reduced pressure. Flashchromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded 316 mg of a brown solid.Preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H₂Owith 0.05% TFA and CH₃CN with 0.05% TFA) afforded 240 mg of a yellowsolid. 2 N HCl in Et₂O (200 mL) was added to a solution of the yellowsolid in 1:1 CH₂Cl₂/MeOH (5 mL) under N₂, and the resulting suspensionwas stirred at 25° C. for 19 h. The suspension was filtered, and thesolid was washed with CH₂Cl₂ and Et₂O to afford the title compound (148mg, 25%) as a yellow solid: ¹H NMR (500 MHz, DMSO-d₆) δ 11.25 (s, 1H),9.15 (br s, 2H), 8.00 (d, J=8.5 Hz, 2H), 7.88 (d, J=8.5 Hz, 2H), 7.78(d, J=7.5 Hz, 1H), 7.54 (d, J=8.5 Hz, 1H), 7.37 (d, J=2.0 Hz, 1H), 7.01(dd, J=8.5, 2.0 Hz, 1H), 6.85 (d, J=2.0 Hz, 1H), 6.70 (dd, J=7.0, 2.0Hz, 1H), 3.40-3.31 (m, 4H), 3.26-3.18 (m, 2H), 3.09-3.14 (m, 2H); ESI MSm/z 424 [M+H]⁺.

Example 13 Preparation of4-((5-Fluoropyridin-2-yl)methoxy)-1-(1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-onedihydrochloride

a) 4-((5-Fluoropyridin-2-yl)methoxy)pyridine 1-oxide (CAS RegistryNumber 1173155-63-9) (WO 2009/089482 to Guzzo et al., which is herebyincorporated by reference in its entirety)

5-Fluoro-2-pyridylbenzylalcohol (3.00 g, 23.6 mmol) was dissolved in DMF(20 mL), and NaH (60% weight dispersion in mineral oil, 0.92 g, 23 mmol)was added. After stirring for 30 minutes, 4-chloropyridine-N-oxide (2.03g, 15.7 mmol) was added, and the reaction mixture was heated for 1 h at120° C. Upon cooling, the mixture was diluted with methylene chlorideand washed with 5% lithium chloride solution (5×), dried andconcentrated. Purification by flash column chromatography (40 g ISCOcolumn eluting with methylene chloride and a methanol/ammonia mixture(10:1); gradient 100% methylene chloride to 90% methylene chloride over30 min at 40 mL/min) provided the title compound (1.76 g, 50%) as a tansolid: ¹H NMR (300 MHz, CDCl₃) δ 8.48 (s, 1H), 8.12 (d, J=7.7 Hz, 2H),7.48-7.46 (m, 2H), 6.90 (d, J=7.7 Hz, 2H), 5.20 (s, 2H).

b) 4-((5-Fluoroyridin-2-yl)methoxy)pyridin-2(1H)-one (CAS RegistryNumber 924311-90-0) (WO 2007/018248 to Ando et al., which is herebyincorporated by reference in its entirety)

4-((5-Fluoropyridin-2-yl)methoxy)pyridine 1-oxide (1.76 g, 7.99 mmol)was reacted according to Example 12 (step c) to provide the titlecompound (1.29 g, 73%) as a yellow solid: ¹H NMR (500 MHz, DMSO-d₆) δ11.12 (s, 1H), 8.59 (d, J=2.9 Hz, 1H), 7.79 (dt, J=8.7, 2.9 Hz, 1H),7.60 (dd, J=8.7, 4.5 Hz, 1H), 7.26 (d, J=7.3 Hz, 1H), 5.95 (dd, J=7.4,2.6 Hz, 1H), 5.78 (d, J=2.5 Hz, 1H), 5.12 (s, 2H).

c)4-((5-Fluoropyridin-2-yl)methoxy)-1-(1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-onedihydrochloride

A suspension of 4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one (102mg, 0.464 mmol), tert-butyl8-bromo-6-tosyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate(265 mg, 0.510 mmol), CuI (106 mg, 0.557 mmol), 8-hydroxyquinoline (13mg, 0.093 mmol) and Cs₂CO₃ (166 mg, 0.510 mmol) in DMSO (10 mL) wasdegassed under reduced pressure for 45 min. The suspension was put underN₂ and stirred at 135° C. overnight. The suspension was cooled,9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resultingsuspension was stirred at 25° C. for 30 min. The suspension was passedthrough a plug of silica gel, and the filtrate was washed with brine.The resulting solution was dried over Na₂SO₄ and concentrated underreduced pressure. Flash chromatography (silica gel, (1:1EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded172 mg of a yellow solid. NaOH (522 mg, 13.8 mmol) was added to asolution of the yellow solid in 1:1 MeOH/CH₂Cl₂ (20 mL) under N₂, andthe resulting suspension was stirred at reflux for 18 h. The reactionwas cooled, H₂O was added, and the resulting solution was extracted withCH₂Cl₂. The combined organic extracts were dried over Na₂SO₄ andconcentrated under reduced pressure. Flash chromatography (silica gel,(1:1 EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100)afforded a white solid. 2 N HCl in Et₂O (200 mL) was added to a solutionof the white solid in 1:1 CH₂Cl₂/MeOH (10 mL) under N₂, and theresulting suspension was stirred at 25° C. for 4 h. The suspension wasfiltered, and the solid was washed with Et₂O to afford the titlecompound (47 mg, 21%) as a white solid: ¹H NMR (500 MHz, DMSO-d₆) δ11.18 (s, 1H), 9.11 (br s, 2H), 8.62 (d, J=3.0 Hz, 1H), 7.83 (ddd,J=9.0, 9.0, 3.0 Hz, 1H), 7.65 (dd, J=9.0, 5.0 Hz, 1H), 7.56 (d, J=7.5Hz, 1H), 7.49 (d, J=8.5 Hz, 1H), 7.25 (d, J=2.0 Hz, 1H), 6.90 (dd,J=8.0, 2.0 Hz, 1H), 6.11 (d, J=8.0, 2.5 Hz, 1H), 5.96 (d, J=2.5 Hz, 1H),5.21 (s, 2H), 3.38-3.29 (m, 4H), 3.20-3.16 (s, 2H), 3.11-3.07 (m, 2H);ESI MS m/z 405 [M+H]⁺.

Example 14 Preparation of4-(Benzyloxy)-1-(3-ethyl-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-onehydrochloride

2-Picoline borane (72 mg, 0.68 mmol) was added to a solution of4-(benzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-onehydrochloride (98 mg, 0.23 mmol) and ethanal (0.04 mL, 1 mmol) in 9:1CH₂Cl₂/AcOH (10 mL), and the resulting solution was stirred at 25° C.for 1 h. A second aliquot of ethanal (0.04 mL, 1 mmol) was added to thesolution, and the resulting solution was stirred at 25° C. for 7 h. H₂Owas added to the solution, and the resulting biphasic system wasneutralized with saturated NaHCO₃ solution. CH₂Cl₂ was added to thebiphasic system, and the phases were separated. The organic phase wasdried over Na₂SO₄ and concentrated under reduced pressure. Flashchromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded an off-white solid. 2 N HClin Et₂O (0.07 mL, 0.07 mmol) was added to a solution of the off-whitesolid in 1:1 CH₂Cl₂/MeOH (10 mL) under N₂, and the resulting solutionwas stirred at 25° C. for 30 min. The solution was diluted with Et₂O,and the resulting suspension was filtered to afford the title compound(41 mg, 38%) as a white powder: mp 246-248° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 10.07 (br s, 1H), 7.59-7.35 (m, 8H), 6.95 (dd, J=8.5, 1.5 Hz,1H), 6.10 (dd, J=7.5, 2.5 Hz, 1H), 6.01-5.96 (m, 1H), 5.15 (s, 2H),3.76-3.05 (m, 13H), 1.31 (t, J=7.0 Hz, 3H); ESI MS m/z 428 [M+H]⁺.

Example 15 Preparation of4-(Benzyloxy)-1-(3-isopropyl-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-onehydrochloride

2-Picoline borane (84 mg, 0.78 mmol) was added to a solution of4-(benzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-onehydrochloride (98 mg, 0.23 mmol) and acetone (1 mL) in 9:1 CH₂Cl₂/AcOH(10 mL), and the resulting solution was stirred at reflux for 48 h. Thesolution was cooled and adjusted to pH 7 with saturated NaHCO₃ solution.The resulting solution was diluted with CH₂Cl₂. The phases wereseparated, and the organic phase was dried over Na₂SO₄ and concentratedunder reduced pressure. Flash chromatography (silica gel, (1:1EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) affordedan off-white solid. Preparative HPLC (Phenomenex Luna C18 (2),250.0×50.0 mm, 10 micron, H₂O with 0.05% TFA and CH₃CN with 0.05% TFA)afforded 30 mg of a white powder. 2 N HCl in Et₂O (0.04 mL, 0.08 mmol)was added to a solution of the white powder in 1:1 CH₂Cl₂/MeOH (10 mL)under N₂ and the resulting solution was stirred at 25° C. for 30 min.The solution was diluted with Et₂O and the resulting suspension wasfiltered to afford the title compound (23 mg, 20%) as a white powder: mp256-258° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.89 (br s, 1H), 7.58-7.52 (m,2H), 7.49-7.35 (m, 6H), 6.96 (dd, J=8.5, 2.0 Hz, 1H), 6.10 (dd, J=7.5,2.5 Hz, 1H), 5.96 (d, J=3.0 Hz, 1H), 5.15 (s, 2H), 3.77-3.62 (m, 7H),3.42-3.24 (m, 4H), 3.18-3.11 (m, 1H), 1.37-1.31 (m, 6H); ESI MS m/z 442[M+H]⁺.

Example 16 Preparation of4-((5-Fluoropyridin-2-yl)methoxy)-1-(3-isopropyl-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-onehydrochloride

2-Picoline borane (125 mg, 1.17 mmol) was added to a solution of4-((5-fluoropyridin-2-yl)methoxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-onehydrochloride (115 mg, 0.234 mmol) and acetone (0.17 mL, 2.3 mmol) in9:1 CH₂Cl₂/AcOH (10 mL), and the resulting solution was stirred atreflux overnight. Acetone (0.8 mL) and 2-picoline borane (125 mg, 1.17mmol) were added to the solution, and the resulting solution was stirredat reflux for 48 h. Acetone (1 mL) and 2-picoline borane (125 mg, 1.17mmol) were added to the solution, and the resulting solution was stirredat reflux for 72 h. The solution was cooled and adjusted to pH 7 withsaturated NaHCO₃ solution. The resulting solution was diluted withCH₂Cl₂. The phases were separated, and the organic phase was dried overNa₂SO₄ and concentrated under reduced pressure. Flash chromatography(silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to0:100) afforded an white powder. Preparative TLC (9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH) afforded 35 mg of a white powder. 2 N HCl in Et₂O(0.04 mL, 0.08 mmol) was added to a solution of the off-white solid in1:1 CH₂Cl₂/MeOH (5 mL) under N₂, and the resulting solution was stirredat 25° C. for 10 min. The solution was concentrated under reducedpressure to afford the title compound (35 mg, 30%) as a white powder: ¹HNMR (500 MHz, DMSO-d₆) δ 9.95 (br s, 1H), 8.62 (d, J=3.0 Hz, 1H), 7.83(ddd, J=8.5, 8.5, 3.0 Hz, 1H), 7.65 (dd, J=9.0, 5.0 Hz, 1H), 7.57-7.52(m, 2H), 7.44 (d, J=2.0 Hz, 1H), 6.95 (dd, J=8.5, 2.0 Hz, 1H), 6.13 (dd,J=8.0, 3.0 Hz, 1H), 5.96 (d, J=2.5 Hz, 1H), 5.22 (s, 2H), 3.78-3.62 (m,6H), 3.43-3.11 (m, 6H), 1.48-1.39 (m, 6H); ESI MS m/z 461 [M+H]⁺.

Example 17 Preparation of4-(Benzyloxy)-1-(3-isopropyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-onehydrochloride

2-Picoline borane (75 mg, 0.70 mmol) was added to a solution of4-(benzyloxy)-1-(1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-onehydrochloride (59 mg, 0.14 mmol) and acetone (1 mL) in 9:1 CH₂Cl₂/AcOH(10 mL), and the resulting solution was stirred at reflux for 24 h.Additional acetone (1 mL) and 2-picoline borane (75 mg, 0.70 mmol) wereadded to the solution, and the resulting solution was stirred at refluxfor 24 h. The solution was cooled, H₂O was added, and the resultingbiphasic solution was adjusted to pH 7 with saturated NaHCO₃ solution.The phases were separated, and the organic phase was dried over Na₂SO₄and concentrated under reduced pressure. Flash chromatography (silicagel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100)afforded a white solid. 2 N HCl in Et₂O (0.04 mL, 0.08 mmol) was addedto a solution of the white solid in 1:1 CH₂Cl₂/MeOH (5 mL) under N₂, andthe resulting solution was stirred at 25° C. for 15 min. The solutionwas concentrated under reduced pressure to afford the title compound (35mg, 54%) as a white powder: mp 152-155° C.; ¹H NMR (500 MHz, DMSO-d₆) δ11.19 (s, 1H), 9.71 (br s, 1H), 7.55-7.36 (m, 7H), 7.26 (d, J=2.0 Hz,1H), 6.91 (dd, J=8.0, 1.5 Hz, 1H), 6.08 (dd, J=7.5, 3.0 Hz, 1H), 5.96(d, J=3.0 Hz, 1H), 5.14 (s, 2H), 3.75-3.61 (m, 3H), 3.36-3.05 (m, 6H),1.36-1.30 (m, 6H); ESI MS m/z 428 [M+H]⁺.

Example 18 Preparation of4-(Benzyloxy)-1-(10-methyl-1,2,3,4,5,10-hexahydroazepino[3,4-b]indol-8-yl)pyridin-2(1H)-onehydrochloride

a) 7-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-one (CAS Registry Number847987-95-5) (WO 2005/023245 to Boggs et al., which is herebyincorporated by reference in its entirety)

MeOH (60 mL) and 7-bromo-2,3,4,9-tetrahydro-1H-carbazole (2.60 g, 10.4mmol) were added to a solution of periodic acid (4.76 g, 20.8 mmol) in1:1 MeOH/H₂O (50 mL), cooled to 0° C., and the resulting slurry waswarmed to ambient temperature with stirring for 18 h. The mixture wasconcentrated to dryness. The resulting solids were dissolved in CHCl₃(100 mL), and the resulting solution was washed with 10% Na₂CO₃ (2×100mL) and 10% Na₂SO₃ (2×50 mL). The organic solution was dried overNa₂SO₄, filtered and concentrated to dryness under reduced pressure. Thesolids were washed with MeOH (75 mL) and dried to yield the titlecompound (1.86 g, 68%) as a yellow solid: ¹H NMR (500 MHz, DMSO-d₆) δ11.73 (s, 1H), 7.64 (d, J=8.5 Hz, 1H), 7.55 (d, J=1.5 Hz, 1H), 7.21 (d,J=8.5, 2.0 Hz, 1H), 2.94 (t, J=6.0 Hz, 2H), 2.56 (t, J=6.0 Hz, 2H),2.17-2.12 (m, 2H).

b) 7-Bromo-9-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-one

Cs₂CO₃ (2.5 g, 7.5 mmol) and iodomethane (0.47 mL, 7.5 mmol) were addedto a solution of 7-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-one (1.7 g,6.3 mmol) in DMF (21 mL), and the resulting mixture was stirred for 4 hat ambient temperature. The reaction was diluted with H₂O (25 mL), andthe resulting solution was stirred for 15 minutes. The resultingprecipitate was collected by filtration, washed with H₂O (200 mL) anddried to yield the title compound (1.5 g, 87%) as an off-white powder:¹H NMR (500 MHz, DMSO-d₆) δ 7.83 (d, J=1.5 Hz, 1H), 7.67 (d, J=8.5 Hz,1H), 7.25 (dd, J=8.5, 1.5 Hz, 1H), 3.98 (s, 3H), 2.96 (t, J=6.0 Hz, 2H),2.57 (t, J=6.0 Hz, 2H), 2.13-2.10 (m, 2H).

c) 7-Bromo-9-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-one oxime

Hydroxylamine hydrochloride (0.56 g, 8.1 mmol) and sodium acetate (0.66g, 8.1 mmol) were added to a suspension of7-bromo-9-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-one (1.5 g, 5.4 mmol)in EtOH (14 mL) and H₂O (5.0 mL), and the resulting suspension washeated at reflux for 18 h. The reaction was cooled and concentrated todryness. The resulting solid was triturated with MeOH (100 mL), and thesolids were dried to yield the title compound (1.4 g, 90%) as anoff-white powder: ¹H NMR (300 MHz, DMSO-d₆) δ 11.14 (s, 1H), 7.66 (s,1H), 7.47 (d, J=8.5 Hz, 1H), 7.15 (dd, J=8.5, 1.0 Hz, 1H), 3.95 (s, 3H),2.79-2.72 (m, 4H), 1.88-1.83 (m, 2H).

d) 8-Bromo-10-methyl-2,3,4,5-tetrahydroazepino[3,4-b]indol-2(10H)-one

A suspension of 7-bromo-9-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-oneoxime (1.4 g, 4.9 mmol) in PPA (32 g) was mechanically rotated in awater bath set at 100° C. for 5 h. The reaction was placed in an icebath and slowly quenched with H₂O (80 mL). The solution was made neutralby addition of 6 N NaOH and extracted with CH₂Cl₂ (6×25 mL). Thecombined organic extracts were concentrated to dryness. Flashpurification (40 g ISCO column, CH₂Cl₂/(80:18:2 CH₂Cl₂/MeOH/NH₄OH),100:0 for 2 column volumes, increased to 0:100 over 20 column volumesand held for 5 column volumes) followed by flash chromatography (40 gISCO column, CH₂Cl₂/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 2 columnvolumes, increased to 70:30 over 20 column volumes) provided the titlecompound (0.21 g, 15%) as a light yellow foam: ¹H NMR (300 MHz, DMSO-d₆)δ 8.21 (t, J=5.7 Hz, 1H), 7.74 (d, J=1.8 Hz, 1H), 7.56 (d, J=8.4 Hz,1H), 7.18 (dd, J=8.4, 1.8 Hz, 1H), 3.85 (s, 3H), 3.15-3.10 (m, 2H), 2.95(t, J=7.2 Hz, 2H), 1.97-1.94 (m, 2H); ESI MS m/z 293 [M+H]⁺.

e) tert-Butyl8-bromo-10-methyl-3,4,5,10-tetrahydroazepino[3,4-b]indole-2(1H)-carboxylate

BH₃.THF (1.0 M solution in THF, 9 mL) was slowly added to a solution of8-bromo-10-methyl-2,3,4,5-tetrahydroazepino[3,4-b]indol-2(10H)-one (0.19g, 0.66 mmol) in THF (11 mL) and the resulting solution was heated atreflux for 18 h. The reaction was cooled and 12 N HCl (˜4 mL) was addedslowly until gas evolution ceased. The resulting solution was dilutedwith H₂O (25 mL) and heated at reflux for 3 h. The solution was cooledand made basic (˜pH 9.5) by slow addition of 6 N NaOH. The resultingsolution was extracted with EtOAc (3×40 mL). The combined organicextracts were washed with brine (50 mL), dried over Na₂SO₄, filtered andconcentrated to afford a crude yellow oil. DMAP (10 mg, catalytic) andBoc₂O (0.19 g, 0.85 mmol) were added to a solution of the yellow oil inCH₂Cl₂ (2.5 mL) under N₂, and the resulting solution was stirred atambient temperature for 18 h. The solution was diluted with H₂O (10 mL)and extracted with CH₂Cl₂ (3×20 mL). The combined organic extracts werewashed with brine (20 mL), dried over Na₂SO₄, filtered and concentratedto dryness under reduced pressure. Flash chromatography (12 g ISCO (1:1hex/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH, 100:0 for 8 column volumes,increased to 50:50 over 12 column volumes and held for 5 column volumes)followed by flash chromatography (12 g ISCO, hexanes/EtOAc, 90:10 for 2column volumes, increased to 50:50 over 20 column volumes and held for 2column volumes) provided the title compound (0.15 g, 60%) as a whitefilm: ¹H NMR (500 MHz, DMSO-d₆) δ 7.64 (s, 1H), 7.39 (d, J=8.5 Hz, 1H),7.10 (d, J=8.0 Hz, 1H), 4.60 (s, 2H), 3.70 (s, 3H), 3.64-3.62 (m, 2H),2.79 (t, J=6.0 Hz, 2H), 1.81-1.80 (m, 2H), 1.36-1.32 (m, 9H).

f)tert-Butyl-8-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-10-methyl-3,4,5,10-tetrahydroazepino[3,4-b]indole-2(1H)-carboxylate

tert-Butyl8-bromo-10-methyl-3,4,5,10-tetrahydroazepino[3,4-b]indole-2(1H)-carboxylate(0.13 g, 0.34 mmol), 4-benzyloxy pyridinone (69 mg, 0.34 mmol), andCs₂CO₃ (0.12 g, 0.38 mmol) were suspended in DMSO (2.0 mL), and the airwas removed under vacuum for 15 min. The system was flushed with Ar, and8-hydroxyquinoline (16 mg, 0.12 mmol) and copper iodide (78 mg, 0.41mmol) were added to the suspension. The evacuation/Ar flushing processwas repeated twice more, and the reaction mixture was heated at 130° C.for 18 h under N₂. The mixture was cooled, diluted with 5:1 MeOH/NH₄OH(10 mL), and the resulting solution was stirred at ambient temperaturefor 30 min. The reaction was further diluted with CH₂Cl₂ (80 mL). Thesolution was filtered through silica gel, and the filtrate wasconcentrated under reduced pressure. The residue was diluted with CH₂Cl₂and washed with brine (4×20 mL). The combined organic extracts weredried over Na₂SO₄, filtered and concentrated to dryness. Flashchromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2CH₂Cl₂/MeOH/NH₄OH), 100:0 for 10 column volumes, increased to 50:50 over20 column volumes and held for 5 column volumes) gave the title compound(56 mg, 32%) as a yellow film: ¹H NMR (500 MHz, CDCl₃) δ 7.55-7.52 (m,1H), 7.42-7.36 (m, 5H), 7.30 (d, J=7.5 Hz, 1H), 7.24 (s, 1H), 7.00 (d,J=8.0 Hz, 1H), 6.10-6.09 (m, 1H), 6.04-6.03 (m, 1H), 5.05 (s, 2H),4.66-4.63 (m, 2H), 3.75-3.67 (m, 5H), 2.92-2.91 (m, 2H), 1.94-1.89 (m,2H), 1.43-1.42 (m, 9H).

g)4-(Benzyloxy)-1-(10-methyl-1,2,3,4,5,10-hexahydroazepino[3,4-b]indol-8-yl)pyridin-2(1H)-one

Trifluoroacetic acid (1.0 mL) was added to a solution oftert-butyl-8-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-10-methyl-3,4,5,10-tetrahydroazepino[3,4-b]indole-2(1H)-carboxylate(54 mg, 0.11 mmol) in CH₂Cl₂ (2.0 mL), and the resulting solution wasstirred at ambient temperature for 30 min. The mixture was carefullyquenched with saturated NaHCO₃ solution until the solution was basic.The mixture was extracted with CH₂Cl₂ (3×25 mL). The combined organicextracts were washed with brine (50 mL), dried over Na₂SO₄ andconcentrated to dryness under reduced pressure. Flash chromatography (12g ISCO column, CH₂Cl₂/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 5 columnvolumes, increased to 0:100 over 20 column volumes and held for 15column volumes) provided the title compound (31 mg, 73%) as an off-whitesolid: ¹H NMR (500 MHz, CDCl₃) δ 7.53 (d, J=8.5 Hz, 1H), 7.43-7.36 (m,5H), 7.30 (d, J=7.5 Hz, 1H), 7.23 (d, J=2.0 Hz, 1H), 6.99 (dd, J=8.0,1.5 Hz, 1H), 6.08 (d, J=2.5 Hz, 1H), 6.03 (dd, J=7.5, 3.0 Hz, 1H), 5.05(s, 2H), 4.10 (s, 2H), 3.64 (s, 3H), 3.23 (t, J=5.5 Hz, 2H), 2.92 (t,J=6.0 Hz, 2H), 1.90-1.86 (s, 2H); ESI MS m/z 400 [M+H]⁺.

h)4-(Benzyloxy)-1-(10-methyl-1,2,3,4,5,10-hexahydroazepino[3,4-b]indol-8-yl)pyridin-2(1H)-onehydrochloride

A solution of4-(benzyloxy)-1-(10-methyl-1,2,3,4,5,10-hexahydroazepino[3,4-b]indol-8-yl)pyridin-2(1H)-one(30 mg, 0.075 mmol) in CH₂Cl₂ (1.0 mL) was treated with anhydrous 1.0 MHCl in diethyl ether (75 μL, 0.075 mmol), and the resulting solution wasstirred at ambient temperature for 1 h. The solution was concentrated todryness, diluted with H₂O and lyophilized to yield the title compound(32 mg, 99%) as a yellow powder: mp 210-218° C. decomp.; ¹H NMR (500MHz, DMSO-d₆) δ 9.04 (s, 2H), 7.59-7.55 (m, 2H), 7.48-7.41 (m, 5H),7.38-7.36 (m, 1H), 6.97 (dd, J=8.5, 2.0 Hz, 1H), 6.10 (dd, J=7.5, 2.5Hz, 1H), 5.97 (d, J=2.5 Hz, 1H), 5.15 (s, 2H), 4.53 (s, 2H), 3.74 (s,3H), 3.49-3.47 (m, 2H), 2.97 (t, J=5.0 Hz, 2H), 1.99-1.97 (m, 2H); ESIMS m/z 400 [M+H]⁺; HPLC (Method A) 97.9% (AUC), t_(R)=14.8 min.

Example 19 Preparation of4-((5-Fluoropyridin-2-yl)methoxy)-1-(10-methyl-1,2,3,4,5,10-hexahydroazepino[3,4-b]indol-8-yl)pyridin2(1H)-one hydrochloride a) tert-Butyl8-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-10-methyl-3,4,5,10-tetrahydroazepino[3,4-b]indole-2(1H)-carboxylate

tert-Butyl8-bromo-10-methyl-3,4,5,10-tetrahydroazepino[3,4-b]indole-2(1H)-carboxylate(0.15 g, 0.39 mmol),4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-one (0.13 g,0.52 mmol), and Cs₂CO₃ (0.14 g, 0.44 mmol) were suspended in DMSO (2.4mL), and the air was removed under vacuum for 15 min. The system wasflushed with Ar, and 8-hydroxyquinoline (17 mg, 0.12 mmol) and copperiodide (98 mg, 0.52 mmol) were added to the suspension. Theevacuation/Ar flushing process was repeated twice more, and the reactionmixture was heated at 130° C. for 18 h under N₂. The mixture was cooled,diluted with 5:1 MeOH/NH₄OH (10 mL), and the resulting solution wasstirred at ambient temperature for 30 min. The reaction was furtherdiluted with CH₂Cl₂ (75 mL). The resulting solution was filtered throughsilica gel, and the filtrate was concentrated under reduced pressure.The residue was diluted with CH₂Cl₂ and washed with brine (4×20 mL). Thecombined organic extracts were dried over Na₂SO₄, filtered andconcentrated to dryness. Flash chromatography (12 g ISCO column, (1:1hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 5 column volumes,increased to 50:50 over 20 column volumes and held for 5 column volumes;increased to 0:100 over 10 column volumes and held for 8 column volumes)provided the title compound (0.12 g, 59%) as a yellow film: ¹H NMR (500MHz, DMSO-d₆) δ 8.61 (d, J=2.5 Hz, 1H), 7.84-7.80 (m, 1H), 7.66-7.64 (m,1H), 7.57 (d, J=7.5 Hz, 1H), 7.49 (d, J=8.5 Hz, 1H), 7.40 (d, J=4.0 Hz,1H), 6.90 (d, J=8.0 Hz, 1H), 6.11 (d, J=8.0, 3.0 Hz, 1H), 5.96 (d, J=2.5Hz, 1H), 5.21 (s, 2H), 4.65-4.63 (m, 2H), 3.72 (s, 3H), 3.67-3.66 (m,2H), 2.86-2.85 (m, 2H), 1.82-1.81 (m, 2H), 1.36-1.34 (m, 9H); ESI MS m/z519 [M+H]⁺.

b)4-((5-Fluoropyridin-2-yl)methoxy)-1-(10-methyl-1,2,3,4,5,10-hexahydroazepino[3,4-b]indol-8-yl)pyridin2(1H)-one

A solution of tert-butyl8-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-10-methyl-3,4,5,10-tetrahydroazepino[3,4-b]indole-2(1H)-carboxylate(0.12 mg, 0.23 mmol) in 4:1 MeOH/CH₂Cl₂ (5.0 mL) was treated withanhydrous 1.0 M HCl in diethyl ether (46 mL), and the resulting solutionwas stirred at ambient temperature for 2 h. The solids were collected byfiltration, washed with Et₂O and dried. Preparative TLC (Analtech, 20×20cm, 1000 microns, 80:18:2 CH₂Cl₂/MeOH/NH₄OH) afforded the title compound(41 mg, 43%) as an off-white powder: ¹H NMR (500 MHz, DMSO-d₆) δ 8.61(d, J=2.5 Hz, 1H), 7.84-7.80 (m, 1H), 7.66-7.64 (m, 1H), 7.55 (d, J=7.5Hz, 1H), 7.46 (d, J=8.5 Hz, 1H), 7.34 (s, 1H), 6.87 (dd, J=8.5, 1.5 Hz,1H), 6.10 (dd, J=7.5, 2.5 Hz, 1H), 5.95 (d, J=3.0 Hz, 1H), 5.21 (s, 2H),4.0 (s, 2H), 3.64 (s, 3H), 3.06 (t, J=5.5 Hz, 2H), 2.83 (t, J=5.5 Hz,2H), 1.77-1.76 (m, 2H); ESI MS m/z 419 [M+H]⁺.

c)4-((5-Fluoropyridin-2-yl)methoxy)-1-(10-methyl-1,2,3,4,5,10-hexahydroazepino[3,4-b]indol-8-yl)pyridin2(1H)-one hydrochloride

1.25 M HCl in MeOH (75 μL, 0.094 mmol) was added to a solution of4-((5-fluoropyridin-2-yl)methoxy)-1-(10-methyl-1,2,3,4,5,10-hexahydroazepino[3,4-b]indol-8-yl)pyridin2(1H)-one (39 mg, 0.094 mmol) in MeOH (2.0 mL), and the resultingsolution was stirred at ambient temperature for 1 h. The mixture wasconcentrated to dryness under reduced pressure to yield the titlecompound (36 mg, 85%) as a light yellow powder: mp 268-275° C. decomp.;¹H NMR (500 MHz, DMSO-d₆) δ 8.62 (d, J=3.0 Hz, 1H), 8.19 (br s, 1H),7.84-7.80 (m, 1H), 7.66-7.64 (m, 1H), 7.58-7.51 (m, 2H), 7.45 (d, J=1.5Hz, 1H), 6.95 (dd, J=8.0, 3.0 Hz, 1H), 6.12 (dd, J=7.5, 2.5 Hz, 1H),5.96 (d, J=3.0 Hz, 1H), 5.21 (s, 2H), 4.39 (s, 2H), 3.71 (s, 3H),3.38-3.36 (m, 2H), 2.95-2.93 (m, 2H), 1.93-1.92 (m, 2H); ESI MS m/z 419[M 30 H]⁺; HPLC (Method A) 98.3% (AUC), t_(R)=13.0 min.

Example 20 Preparation of1-(10-Methyl-1,2,3,4,5,10-hexahydroazepino[3,4-b]indol-8-yl)-4-(5-trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-onehydrochloride a) tert-Butyl10-methyl-8-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-3,4,5,10-tetrahydroazepino[3,4-b]indole-2(1H)-carboxylate

tert-Butyl8-bromo-10-methyl-3,4,5,10-tetrahydroazepino[3,4-b]indole-2(1H)-carboxylate(0.15 g, 0.39 mmol),4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (0.13 g, 0.54mmol), and Cs₂CO₃ (0.19 g, 0.60 mmol) were suspended in DMSO (3.3 mL),and the air was removed under vacuum for 15 min. The system was flushedwith Ar, and 8-hydroxyquinoline (23 mg, 0.16 mmol) and copper iodide(0.13 g, 0.59 mmol) were added to the suspension. The evacuation/Arflushing process was repeated twice more, and the reaction mixture washeated at 130° C. for 18 h under N₂. The mixture was cooled, dilutedwith 5:1 MeOH/NH₄OH (15 mL), and the resulting solution was stirred atambient temperature for 30 min. The reaction was further diluted withCH₂Cl₂ (75 mL). The resulting solution was filtered through silica gel,and the filtrate was concentrated under reduced pressure. The residuewas diluted with CH₂Cl₂ and washed with brine (3×25 mL). The organicsolution was dried over Na₂SO₄, filtered and concentrated to dryness.Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2CH₂Cl₂/MeOH/NH₄OH), 100:0 for 5 column volumes, increased to 50:50 over20 column volumes and held for 5 column volumes; increased to 0:100 over20 column volumes and held for 5 column volumes) followed by preparativeHPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H₂O with 0.05%TFA and CH₃CN with 0.05% TFA) gave the title compound (62 mg, 20%) as ayellow solid: ¹H NMR (500 MHz, CDCl₃) δ 9.00 (s, 1H), 8.06 (d, J=8.5 Hz,1H), 7.91 (d, J=7.5 Hz, 1H), 7.60-7.57 (m, 2H), 7.35-7.32 (m, 1H),7.28-7.26 (s, 1H), 7.08-7.02 (m, 2H), 4.68-4.64 (m, 2H), 3.78-3.74 (m,4H), 3.71-3.69 (m, 1H), 2.95-2.94 (m, 2H), 1.96-1.91 (m, 2H), 1.43 (s,9H); ESI MS m/z 539 [M+H]⁺.

b)1-(10-Methyl-1,2,3,4,5,10-hexahydroazepino[3,4-b]indol-8-yl)-4-(5-trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-onehydrochloride

Anhydrous 1.0 M HCl in diethyl ether (23 mL) was added to a solution oftert-butyl10-methyl-8-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-3,4,5,10-tetrahydroazepino[3,4-b]indole-2(1H)-carboxylate(60 mg, 0.11 mmol) in 4:1 MeOH/CH₂Cl₂ (5.0 mL), and the resultingsolution was stirred at ambient temperature for 2 h. The solids werecollected by filtration, washed with Et₂O and dried to yield the titlecompound (47 mg, 87%) as a yellow powder: mp 288-296° C. decomp; ¹H NMR(500 MHz, DMSO-d₆) δ 9.15 (s, 1H), 9.12 (br s, 2H), 8.40-8.34 (m, 2H),7.84 (d, J=7.5 Hz, 1H), 7.64 (d, J=8.5 Hz, 1H), 7.62 (d, J=1.5 Hz, 1H),7.28 (d, J=2.0 Hz, 1H), 7.10-7.06 (m, 2H), 4.55 (s, 2H), 3.77 (s, 3H),3.50-3.49 (m, 2H), 3.01-2.98 (m, 2H), 2.00-1.98 (m, 2H); ESI MS m/z 439[M+H]⁺; HPLC (Method A) 99.8% (AUC), t_(R)=14.5 min.

Example 21 Preparation of4-(Benzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-onehydrochloride

a) 7-Bromo-2,3,4,9-tetrahydro-1H-carbazole (CAS Registry Number78863-99-7) (Plant et al., Journal of the Chemical Society, 237-239(1939), which is hereby incorporated by reference in its entirety)

Cyclohexanone (7.7 mL, 73 mmol) was added to a suspension of3-bromophenyl hydrazine hydrochloride (15 g, 67 mmol) in EtOH (150 mL)and 12 N HCl (30 mL), and the resulting suspension was heated at refluxfor 1 h. The suspension was cooled and diluted with H₂O (200 mL). Theresulting solids were collected by filtration. The solids were dissolvedin EtOAc, and the solution was made basic with saturated NaHCO₃solution. The resulting solution was extracted with EtOAc (2×100 mL).The combined organic extracts were dried over Na₂SO₄, filtered andconcentrated to dryness. The solids were suspended in CH₂Cl₂ (˜100 mL)and collected by filtration. The solids were washed with MeOH (50 mL)and dried under reduced pressure to provide the title compound (5.74 g,33%) as a white solid: ¹H NMR (500 MHz, CD₃OD) δ 7.35 (d, J=1.5 Hz, 1H),7.22 (d, J=8.0 Hz, 1H), 7.02 (dd, J=8.0, 1.5 Hz, 1H), 2.70 (t, J=6.0 Hz,2H), 2.64 (t, J=5.5 Hz, 2H), 1.91-1.84 (m, 4H).

b) 7-Bromo-2,3-dihydro-1H-carbazol-4(9H)-one

A solution 7-bromo-2,3,4,9-tetrahydro-1H-carbazole (2.87 g, 11.5 mmol)in THF (103 mL) and H₂O (11.5 mL) was cooled to 0° C. and treated with asolution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (5.23 g, 23.1mmol) in THF (46 mL) at such a rate that the reaction mixture did notexceed 4° C. The resulting solution was allowed to stir for anadditional 45 min at 0° C. The solution was concentrated to drynessunder reduced pressure. The resulting solids were suspended in EtOAc(100 mL) and saturated NaHCO₃ solution (300 mL). The solids werecollected by filtration and washed with additional saturated NaHCO₃solution (400 mL) followed by H₂O (150 mL). The solid was dried toprovide the title compound (2.46 g, 81%) as a light pink solid: ¹H NMR(500 MHz, DMSO-d₆) δ 11.97 (s, 1H), 7.86 (d, J=8.5 Hz, 1H), 7.58 (d,J=1.5 Hz, 1H), 7.27 (dd, J=8.5, 2.0 Hz, 1H), 2.95 (t, J=6.0 Hz, 2H),2.42 (t, J=6.0 Hz, 2H), 2.14-2.09 (m, 2H); ESI MS m/z 263 [M+H]⁺.

c) 7-Bromo-9-methyl-2,3-dihydro-1H-carbazol-4(9H)-one

Sodium hydride (60% dispersion in oil, 0.342 g, 8.55 mmol) was added toa solution of 7-bromo-2,3-dihydro-1H-carbazol-4(9H)-one (2.46 g, 9.35mmol) in DMF (33 mL) at room temperature under N₂ and stirred for 15min. Methyl iodide (1.99 mL, 14.0 mmol) was added to the solution, andthe resulting solution was stirred for 2 h at ambient temperature. Themixture was quenched with H₂O (80 mL), upon which a solid precipitatedout of solution. The solids were collected by filtration and were washedthoroughly with water followed by hexanes to provide the title compound(2.43 g, 94%) as a tan solid: ¹H NMR (500 MHz, DMSO-d₆) δ 7.90 (d, J=8.5Hz, 1H), 7.81 (d, J=1.5 Hz, 1H), 7.32 (dd, J=8.5, 1.5 Hz, 1H), 3.71 (s,3H), 2.97 (t, J=6.0 Hz, 2H), 2.42 (t, J=6.0 Hz, 2H), 2.15-2.10 (m, 2H).

d) 7-Bromo-9-methyl-2,3-dihydro-1H-carbazol-4(9H)-one oxime

Hydroxylamine hydrochloride (3.21 g, 46.5 mmol) and sodium acetate (3.81g, 46.5 mmol) were added to a suspension of7-bromo-9-methyl-2,3-dihydro-1H-carbazol-4(9H)-one (8.61 g, 30.9 mmol)in EtOH (79.0 mL) and H₂O (27.0 mL), and the resulting suspension washeated at reflux for 20 h. The reaction was cooled to ˜40° C., and thesolids were collected by filtration. The solids were washed with H₂O andEtOH. The solids were divided into two batches of 3.93 g and 4.08 g andrecrystallized in CH₃CN (500 mL per batch). The material was allowed tocrystallize for two days the resulting crystals were collected byfiltration to afford the title compound (6.31 g, 70%) as an off-whitecrystalline solid: ¹H NMR (500 MHz, DMSO-d₆) δ 10.33 (s, 1H), 7.82 (d,J=8.5 Hz, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.20 (dd, J=8.0, 1.5 Hz, 1H),3.66 (s, 3H), 2.81 (t, J=6.0 Hz, 2H), 2.66 (t, J=6.0 Hz, 2H), 1.94-1.91(m, 2H). Additional material was obtained by concentrating the filtrateto 200 mL and collecting the resulting solids to afford the titlecompound (1.22 g, 13%) as an off-white powder.

e) 8-Bromo-6-methyl-2,3,4,5-tetrahydroazepino[4,3-b]indol-1(6H)-one

Two batches of a suspension of7-bromo-9-methyl-2,3-dihydro-1H-carbazol-4(9H)-one oxime (3.76 g, 12.8mmol) in PPA (58 g) were mechanically rotated in a water bath set at100° C. for 4.5 h. The batches were placed in an ice bath and slowlyquenched with H₂O. The flasks were sonicated, and the resulting solidswere isolated by filtration. The solids were washed with water, 1N NaOH(300 mL), and copious H₂O until ˜pH 7 was reached. The resulting solidswere dried to afford the title compound (7.15 g, 95%) as a slightly pinksolid: ¹H NMR (300 MHz, DMSO-d₆) δ 8.18 (d, J=8.4 Hz, 1H), 7.73 (d,J=1.5 Hz, 1H), 7.58-7.55 (m, 1H), 7.20 (dd, J=8.4, 1.5 Hz, 1H), 3.67 (s,3H), 3.20-3.16 (m, 2H), 3.08 (t, J=6.6 Hz, 2H), 2.07-2.00 (m, 2H).

f) tert-Butyl8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

BH₃.THF (1.0 M solution in THF, 298 mL) was slowly added to a solutionof 8-bromo-6-methyl-2,3,4,5-tetrahydroazepino[4,3-b]indol-1(6H)-one(6.50 g, 22 mmol) in THF (371 mL), and the resulting solution was heatedat reflux for 24 h. The reaction was cooled, and 12 N HCl solution (˜40mL) was added slowly over 1 h. The solution was diluted with H₂O (400mL) and reheated at reflux for 4.5 h. The solution was cooled and madebasic (pH ˜9.5) by slow addition of 6 N NaOH. The solution was extractedwith EtOAc (3×75 mL). The combined organic extracts were dried overNa₂SO₄, filtered and concentrated to provide a crude yellow oil. DMAP(300 mg, catalytic) and Boc₂O (6.3 g, 29 mmol) were added to a solutionof the yellow oil in CH₂Cl₂ (84 mL) under N₂, and the resulting solutionwas stirred at ambient temperature for 18 h. The solution was dilutedwith H₂O and extracted with CH₂Cl₂ (3×25 mL). The combined organicextracts were dried over Na₂SO₄, filtered and concentrated to drynessunder reduced pressure. Flash chromatography (120 g ISCO hexanes/EtOAc,95:5 for 2 column volumes, increased to 50:50 over 12 column volumes andheld for 4 column volumes; increased to 0:100 over 10 column volumes)provided the title compound (6.21 g, 72%) as an off-white solid: ¹H NMR(300 MHz, DMSO-d₆) δ 7.61 (d, J=1.5 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H),7.09 (dd, J=8.4, 1.5 Hz, 1H), 4.52-4.49 (m, 2H), 3.62-3.59 (m, 5H),2.94-2.90 (m, 2H), 1.87-1.85 (m, 2H), 1.33-1.21 (m, 9H).

g) tert-Butyl8-(4-benzyloxy)-2-oxopyridin-1(2H)-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

tert-Butyl8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(0.12 g, 0.33 mmol), 4-benzyloxy pyridinone (65 mg, 0.33 mmol), andCs₂CO₃ (0.12 g, 0.38 mmol) were suspended in DMSO (2.0 mL), and the airwas removed under vacuum for 15 min. The system was flushed with Ar, and8-hydroxyquinoline (14 mg, 0.098 mmol) and copper iodide (74 mg, 0.39mmol) were added to the suspension. The evacuation/Ar flushing processwas repeated twice more, and the reaction mixture was heated at 133° C.for 18 h under N₂. The mixture was cooled, diluted with 5:1 MeOH/NH₄OH(25 mL), and the resulting solution was stirred at ambient temperaturefor 30 min. The reaction was further diluted with CH₂Cl₂ (75 mL), andthe resulting solution was filtered through silica gel. The filtrate wasconcentrated under reduced pressure. The residue was diluted with CH₂Cl₂and washed with H₂O (1×25 mL) and brine (3×50 mL). The organic solutionwas dried over Na₂SO₄, filtered and concentrated to dryness. Flashchromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2CH₂Cl₂/MeOH/NH₄OH), 100:0 for 10 column volumes, increased to 50:50 over20 column volumes and held for 5 column volumes) gave the title compound(88 mg, 54%) as a yellow foam: ¹H NMR (500 MHz, CDCl₃) δ 7.63-7.52 (m,2H), 7.42-7.36 (m, 5H), 7.31 (d, J=7.5 Hz, 1H), 6.99 (d, J=7.0 Hz, 1H),6.10-6.09 (m, 1H), 6.04-6.03 (m, 1H), 5.05 (s, 2H), 4.71-4.62 (m, 2H),4.14-4.10 (m, 5H), 2.97-2.96 (m, 2H), 2.04-2.03 (m, 2H), 1.44-1.37 (m,9H).

h) 4-(Benzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one

Trifluoroacetic acid (1.0 mL) was added to a solution of tert-butyl8-(4-benzyloxy)-2-oxopyridin-1(2H)-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(88 mg, 0.18 mmol) in CH₂Cl₂ (1.0 mL) and the resulting solution wasstirred at ambient temperature for 1 h. The mixture was carefully madebasic with saturated NaHCO₃ solution. The mixture was extracted withCH₂Cl₂ (3×20 mL). The combined organic extracts were washed with brine(125 mL), dried over Na₂SO₄, and concentrated under reduced pressure todryness. Flash chromatography (12 g ISCO column, CH₂Cl₂/(80:18:2CH₂Cl₂/MeOH/NH₄OH), 100:0 for 5 column volumes, increased to 0:100 over20 column volumes and held for 5 column volumes) provided the titlecompound (46 mg, 69%) as an off-white solid: ¹H NMR (500 MHz, CDCl₃) δ7.49 (d, J=8.5 Hz, 1H), 7.43-7.36 (m, 5H), 7.30 (d, J=7.5 Hz, 1H), 7.23(d, J=1.5 Hz, 1H), 6.79 (dd, J=8.5, 2.0 Hz, 1H), 6.08 (d, J=3.0 Hz, 1H),6.03 (dd, J=8.0, 3.0 Hz, 1H), 5.05 (s, 2H), 4.08 (s, 2H), 3.66 (s, 3H),3.25 (t, J=5.5 Hz, 2H), 2.98 (t, J=5.5 Hz, 2H), 1.94-1.89 (m, 2H); ESIMS m/z 400 [M+H]⁺.

i)4-(Benzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-onehydrochloride

A solution of4-(benzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one(45 mg, 0.11 mmol) in CH₂Cl₂ (2.0 mL) was treated with anhydrous 1.0 MHCl in diethyl ether (0.11 mL, 0.11 mmol), and the resulting solutionwas stirred at ambient temperature for 1 h. The solution wasconcentrated to dryness, diluted with H₂O and lyophilized to yield thetitle compound (47 mg, 95%) as an off-white powder: mp 283-287° C.,decomp.; ¹H NMR (500 MHz, DMSO-d₆) δ 8.96 (s, 2H), 7.64 (d, J=8.0 Hz,1H), 7.55 (d, J=7.5 Hz, 1H), 7.48-7.41 (m, 5H), 7.38-7.36 (m, 1H), 6.99(dd, J=8.5, 2.0 Hz, 1H), 6.10 (dd, J=7.5, 2.5 Hz, 1H), 5.96 (d, J=3.0Hz, 1H), 5.15 (s, 2H), 4.44-4.43 (m, 2H), 3.71 (s, 3H), 3.45-3.43 (m,2H), 3.09 (t, J=6.0 Hz, 2H), 2.06-2.04 (m, 2H); ESI MS m/z 400 [M+H]⁺;HPLC (Method A) 98.2% (AUC), t_(R)=14.3 min.

Example 22 Preparation of4-((5-Fluoropyridin-2-yl)methoxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-)pyridin-2(1H)-onehydrochloride a) tert-Butyl8-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

tert-Butyl8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(0.15 g, 0.39 mmol), 4-(5-(fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one(0.11 g, 0.52 mmol), and Cs₂CO₃ (0.14 g, 0.44 mmol) were suspended inDMSO (2.4 mL), and the air was removed under vacuum for 15 min. Thesystem was flushed with Ar, and 8-hydroxyquinoline (17 mg, 0.12 mmol)and copper iodide (98 mg, 0.52 mmol) were added to the suspension. Theevacuation/Ar flushing process was repeated twice more, and the reactionmixture was heated at 130° C. for 18 h under N₂. The mixture was cooled,diluted with 5:1 MeOH/NH₄OH (15 mL), and the resulting solution wasstirred at ambient temperature for 30 min. The reaction was furtherdiluted with CH₂Cl₂ (75 mL) and filtered through silica gel. Thefiltrate was concentrated under reduced pressure. The residue wasdiluted with CH₂Cl₂ and washed with brine (3×25 mL). The organicsolution was dried over Na₂SO₄, filtered and concentrated to dryness.Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2CH₂Cl₂/MeOH/NH₄OH), 100:0 for 5 column volumes, increased to 50:50 over20 column volumes and held for 5 column volumes; increased to 0:100 over10 column volumes and held for 5 column volumes) followed by preparativeHPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H₂O with 0.05%TFA and CH₃CN with 0.05% TFA) gave the title compound (0.12 g, 57%) asan off-white film: ¹H NMR (500 MHz, DMSO-d₆) δ 8.61 (d, J=3.0 Hz, 1H),7.84-7.80 (m, 1H), 7.66-7.64 (m, 1H), 7.56 (d, J=7.5 Hz, 1H), 7.47 (d,J=8.5 Hz, 1H), 7.38 (s, 1H), 6.92 (d, J=8.5 Hz, 1H), 6.11 (d, J=7.5 Hz,1H), 5.96 (d, J=3.0 Hz, 1H), 5.21 (s, 2H), 4.58 (s, 2H), 3.66-3.64 (m,5H), 2.99-2.97 (m, 2H),1.93-1.89 (m, 2H), 1.35-1.28 (m, 9H).

b)4-((5-Fluoropyridin-2-yl)methoxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl))pyridin-2(1H)-onehydrochloride

A solution of4-(2-fluoro-4-methoxyphenyl)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one(53 mg, 0.093 mmol) in 1.25 M HCl in MeOH (6.0 mL) was stirred atambient temperature for 18 h. The mixture was concentrated to drynessunder reduced pressure to provide the title compound (49 mg,quantitative) as a brown-yellow powder: ¹H NMR (500 MHz, DMSO-d₆) δ 9.17(s, 2H), 8.62 (s, 1H), 8.19 (d, J=8.0 Hz, 1H), 7.85-7.81 (m, 1H),7.67-7.63 (m, 1H), 7.58 (d, J=7.5 Hz, 1H), 7.48 (d, J=1.5 Hz, 1H), 6.99(dd, J=8.5, 1.5 Hz, 1H), 6.14 (dd, J=7.5, 2.5 Hz, 1H), 5.97 (d, J=3.0Hz, 1H), 5.22 (s, 2H), 4.43-4.41 (m, 2H), 3.71 (s, 3H), 3.43-3.39 (m,2H), 3.09 (t, J=5.0 Hz, 2H), 2.07-2.05 (m, 2H); ESI MS m/z 419 [M+H]⁺;HPLC (Method A) 96.5% (AUC), t_(R)=12.5 min.

Example 23 Preparation of1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-onehydrochloride a) tert-Butyl6-methyl-8-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

tert-Butyl8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(0.15 g, 0.39 mmol),4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (0.13 g, 0.54mmol), and Cs₂CO₃ (0.14 g, 0.44 mmol) were suspended in DMSO (2.4 mL),and the air was removed under vacuum for 15 min. The system was flushedwith Ar, and 8-hydroxyquinoline (17 mg, 0.12 mmol) and copper iodide (98mg, 0.52 mmol) were added to the suspension. The evacuation/Ar flushingprocess was repeated twice more, and the reaction mixture was heated at130° C. for 18 h under N₂. The mixture was cooled, diluted with 5:1MeOH/NH₄OH (15 mL), and the resulting solution was stirred at ambienttemperature for 30 min. The reaction was further diluted with CH₂Cl₂ (75mL). The resulting solution was filtered through silica gel and thefiltrate was concentrated under reduced pressure. The residue wasdiluted with CH₂Cl₂ and washed with brine (3×25 mL). The organicsolution was dried over Na₂SO₄, filtered and concentrated to dryness.Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2CH₂Cl₂/MeOH/NH₄OH), 100:0 for 5 column volumes, increased to 50:50 over20 column volumes and held for 5 column volumes; increased to 0:100 over10 column volumes and held for 8 column volumes) followed by preparativeHPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H₂O with 0.05%TFA and CH₃CN with 0.05% TFA) gave the title compound (84 mg, 40%) as ayellow film: ¹H NMR (500 MHz, CDCl₃) δ 9.00 (s, 1H), 8.06 (d, J=8.0 Hz,1H), 7.91 (d, J=8.0 Hz, 1H), 7.59-7.56 (m, 2H), 7.33 (s, 1H), 7.26 (s,1H), 7.07-7.02 (m, 2H), 4.73-4.64 (m, 2H), 3.76-3.67 (m, 5H), 2.99-2.98(m, 2H), 2.05-2.04 (m, 2H), 1.44-1.38 (m, 9H); ESI MS m/z 539 [M+H]⁺.

b)1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-onehydrochloride

A solution of tert-butyl6-methyl-8-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(80 mg, 0.20 mmol) in 5:1 MeOH/CH₂Cl₂ (6.0 mL) was treated withanhydrous 1.0 M HCl in diethyl ether (32 mL), and the resultingsuspension was stirred at ambient temperature for 1 h. The solids werecollected by filtration, washed with Et₂O and dried to yield the titlecompound (58 mg, 85%) as a yellow powder: mp 264-270° C. decomp.; ¹H NMR(500 MHz, DMSO-d₆) δ 9.15 (s, 1H), 8.89 (s, 2H), 8.39 (dd, J=8.5, 2.0Hz, 1H), 8.34 (d, J=8.0 Hz, 1H), 7.83 (d, J=7.5 Hz, 1H), 7.70 (d, J=8.5Hz, 1H), 7.62 (d, J=1.5 Hz, 1H), 7.28 (d, J=1.5 Hz, 1H), 7.11 (dd,J=8.0, 1.5 Hz, 1H), 7.07 (d, J=7.5, 2.0 Hz, 1H), 4.47 (s, 2H), 3.74 (s,3H), 3.47-3.45 (m, 2H), 3.11 (t, J=5.0 Hz, 2H), 2.08-2.06 (m, 2H); ESIMS m/z 439 [M+H]⁺; HPLC (Method A) 95.1% (AUC), t_(R)=14.7 min.

Example 24 Preparation of1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-onehydrochloride a) tert-Butyl6-methyl-8-(2-oxo-4((6-trifluoromethyl)pyridin-3-yl)methoxy)pyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

tert-Butyl8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(0.15 g, 0.39 mmol),4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-one (0.14 g,0.52 mmol), and Cs₂CO₃ (0.14 g, 0.44 mmol) were suspended in DMSO (2.4mL), and the air was removed under vacuum for 15 min. The system wasflushed with Ar, and 8-hydroxyquinoline (17 mg, 0.12 mmol) and copperiodide (98 mg, 0.52 mmol) were added to the suspension. Theevacuation/Ar flushing process was repeated twice more, and the reactionmixture was heated at 130° C. for 18 h under N₂. The mixture was cooled,diluted with 5:1 MeOH/NH₄OH (10 mL), and the resulting solution wasstirred at ambient temperature for 30 min. The reaction was furtherdiluted with CH₂Cl₂ (75 mL). The resulting solution was filtered throughsilica gel, and the filtrate concentrated under reduced pressure. Theresidue was diluted with CH₂Cl₂ and washed with brine (4×20 mL). Theorganic solution was dried over Na₂SO₄, filtered and concentrated todryness. Flash chromatography (12 g ISCO column, (1:1hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 5 column volumes,increased to 50:50 over 20 column volumes and held for 5 column volumes;increased to 0:100 over 10 column volumes and held for 8 column volumes)followed by preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10micron, H₂O with 0.05% TFA and CH₃CN with 0.05% TFA) gave the titlecompound (61 mg, 27%) as an off-white foam: ¹H NMR (500 MHz, DMSO-d₆) δ8.89 (s, 1H), 8.19 (dd, J=8.0, 1.5 Hz, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.59(d, J=7.5 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.39 (s, 1H), 6.92 (d, J=8.0Hz, 1H), 6.13 (dd, J=7.5, 2.5 Hz, 1H), 6.01 (d, J=3.0 Hz, 1H), 5.34 (s,2H), 4.58 (s, 2H), 3.66-3.64 (m, 5H), 2.98-2.97 (m, 2H), 1.93-1.89 (m,2H), 1.35-1.28 (m, 9H).

b)1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-onehydrochloride

A solution of tert-butyl6-methyl-8-(2-oxo-4((6-trifluoromethyl)pyridin-3-yl)methoxy)pyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(53 mg, 0.093 mmol) in 1.25 M HCl in MeOH (6.0 mL) was stirred atambient temperature for 18 h. The solution was concentrated to dryness,diluted with H₂O and lyophilized to yield the title compound (49 mg,quant.) as a brown-yellow powder: ¹H NMR (500 MHz, DMSO-d₆) δ 9.13 (s,2H), 8.89 (s, 1H), 8.19 (d, J=8.0 Hz, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.64(d, J=8.5 Hz, 1H), 7.59 (d, J=7.5 Hz, 1H), 7.48 (d, J=1.5 Hz, 1H), 6.99(dd, J=8.5, 1.5 Hz, 1H), 6.15 (dd. J=7.5, 2.5 Hz, 1H), 6.01 (d, J=2.5Hz, 1H), 5.35 (s, 2H), 4.42 (s, 2H), 3.71 (s, 3H), 3.44-3.42 (m, 2H),3.10-3.09 (m, 2H), 2.07-2.06 (m, 2H); ESI MS m/z 469 [M+H]⁺; HPLC(Method A) 98.8% (AUC), t_(R)=14.2 min.

Example 25 Preparation of1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(2-(trifluoromethyl)pyrimdin-5-yl)pyridin-2(1H)-onehydrochloride a) tert-Butyl6-methyl-8-(2-oxo-4-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-1(2H)-yl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

tert-Butyl8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(0.15 g, 0.39 mmol),4-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2(1H)-one (0.12 g, 0.52mmol), and Cs₂CO₃ (0.14 g, 0.44 mmol) were suspended in DMSO (2.4 mL),and the air was removed under vacuum for 15 min. The system was flushedwith Ar, and 8-hydroxyquinoline (17 mg, 0.12 mmol) and copper iodide (98mg, 0.52 mmol) were added to the suspension. The evacuation/Ar flushingprocess was repeated twice more, and the reaction mixture was heated at130° C. for 18 h under N₂. The mixture was cooled, diluted with 5:1MeOH/NH₄OH (20 mL), and the resulting solution was stirred at ambienttemperature for 30 min. The reaction was further diluted with CH₂Cl₂ (75mL). The resulting solution was filtered through silica gel, and thefiltrate was concentrated under reduced pressure. The residue wasdiluted with CH₂Cl₂ and washed with brine (3×20 mL). The organicsolution was dried over Na₂SO₄, filtered and concentrated to drynessunder reduced pressure. Flash chromatography (12 g ISCO column, (1:1hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 5 column volumes,increased to 50:50 over 20 column volumes and held for 5 column volumes;increased to 0:100 over 10 column volumes and held for 8 column volumes)followed by preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10micron, H₂O with 0.05% TFA and CH₃CN with 0.05% TFA) gave the titlecompound (40 mg, 19%) as a yellow film: ¹H NMR (500 MHz, DMSO-d₆) δ 9.50(s, 2H), 7.90-7.88 (m, 1H), 7.54-7.50 (m, 2H), 7.12 (d, J=1.5 Hz, 1H),7.04-7.02 (m, 1H), 6.85 (dd, J=7.0, 2.0 Hz, 1H), 4.60 (s, 2H), 3.69-3.65(m, 5H), 3.01-3.00 (m, 2H), 1.94-1.91 (m, 2H), 1.36-1.30 (m, 9H).

b)1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(2-(trifluoromethyl)pyrimdin-5-yl)pyridin-2(1H)-onehydrochloride

A solution of tert-butyl6-methyl-8-(2-oxo-4-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-1(2H)-yl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(38 mg, 0.071 mmol) in 1.25 M HCl in MeOH (10.0 mL) was stirred atambient temperature for 18 h. The solution was concentrated to dryness,diluted with H₂O and lyophilized to provide the title compound (28 mg,83%) as a yellow solid: ¹H NMR (500 MHz, DMSO-d₆) δ 9.51 (s, 2H), 8.93(s, 2H), 7.89 (d, J=7.5 Hz, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.60 (d, J=1.5Hz, 1H), 7.12-7.09 (m, 2H), 6.87 (dd, J=7.5, 2.0 Hz, 1H), 4.47 (s, 2H),3.74 (s, 3H), 3.46-3.40 (m, 2H), 3.12-3.11 (m, 2H), 2.08-2.07 (m, 2H);ESI MS m/z 440 [M+H]⁺; HPLC (Method A) 98.2% (AUC), t_(R)=14.1 min.

Example 26 Preparation of1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4(4-trifluoromethyl)phenyl)pyridin-2(1H)-onehydrochloride a) tert-Butyl6-methyl-8-(2-oxo-4(4-trifuoromethyl)phenyl)pyridine-1(2H)-yl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

tert-Butyl8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(0.15 g, 0.39 mmol), 4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one(0.13 g, 0.54 mmol), and Cs₂CO₃ (0.14 g, 0.44 mmol) were suspended inDMSO (2.4 mL), and the air was removed under vacuum for 15 min. Thesystem was flushed with Ar, and 8-hydroxyquinoline (17 mg, 0.12 mmol)and copper iodide (98 mg, 0.52 mmol) were added to the suspension. Theevacuation/Ar flushing process was repeated twice more, and the reactionmixture was heated at 130° C. for 18 h under N₂. The mixture was cooled,diluted with 5:1 MeOH/NH₄OH (20 mL), and the resulting solution wasstirred at ambient temperature for 30 min. The reaction was furtherdiluted with CH₂Cl₂ (75 mL). The resulting solution was filtered throughsilica gel, and the filtrate was concentrated under reduced pressure.The residue was diluted with CH₂Cl₂ and washed with brine (3×20 mL). Theorganic solution was dried over Na₂SO₄, filtered and concentrated todryness under reduced pressure. Flash chromatography (12 g ISCO column,(1:1 hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 5 columnvolumes, increased to 50:50 over 20 column volumes and held for 4 columnvolumes; increased to 0:100 over 10 column volumes and held for 5 columnvolumes) followed by preparative HPLC (Phenomenex Luna C18 (2),250.0×50.0 mm, 10 micron, H₂O with 0.05% TFA and CH₃CN with 0.05% TFA)gave the title compound (81 mg, 38%) as a yellow film: ¹H NMR (500 MHz,CDCl₃) δ 7.74 (s, 4H), 7.68-7.51 (m, 2H), 7.33 (s, 1H), 7.07-7.04 (m,1H), 6.92-6.91 (m, 1H), 6.49 (d, J=6.0 Hz, 1H), 4.72-4.64 (m, 2H),3.76-3.67 (m, 5H), 2.98 (t, J=6.0 Hz, 2H), 2.06-2.02 (m, 2H), 1.44-1.38(m, 9H); ESI MS m/z 538 [M+H]⁺.

b)1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4(4-trifluoromethyl)phenyl)pyridin-2(1H)-onehydrochloride

A solution of tert-butyl6-methyl-8-(2-oxo-4(4-trifuoromethyl)phenyl)pyridine-1(2H)-yl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(75 mg, 0.13 mmol) in 4:1 MeOH/CH₂Cl₂ (5.0 mL) was treated withanhydrous 1.0 M HCl in diethyl ether (28 mL), and the reaction mixturewas stirred at ambient temperature for 2 h. The solids were collected byfiltration, washed with Et₂O and dried to yield the title compound (57mg, 86%) as a yellow powder: mp 264-270° C. decomp.; ¹H NMR (500 MHz,DMSO-d₆) δ 9.01 (s, 2H), 8.01 (d, J=8.5 Hz, 2H), 7.88 (d, J=8.0 Hz, 2H),7.80 (d, J=7.0 Hz, 1H), 7.69 (d, J=8.5 Hz, 1H), 6.60 (d, J=2.0 Hz, 1H),7.10 (d, J=8.5, 2.0 Hz, 1H), 6.86 (d, J=2.0 Hz, 1H), 6.72 (dd, J=7.5,2.5 Hz, 1H), 4.55-4.46 (m, 2H), 3.73 (s, 3H), 3.46-3.45 (m, 2H), 3.11(t, J=5.5 Hz, 2H), 2.08-2.06 (m, 2H); ESI MS m/z 438 [M+H]⁺; HPLC(Method A) 97.1% (AUC), t_(R)=15.7 min.

Example 27 Preparation of1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-onehydrochloride a) tert-Butyl6-methyl-8-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-1(2H)-yl)3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

tert-Butyl8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(0.11 g, 0.29 mmol),4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one (83 g, 0.35 mmol)and Cs₂CO₃ (0.10 g, 0.32 mmol) were suspended in DMSO (1.0 mL), and theair was removed under vacuum for 15 min. The system was flushed with Ar,and 8-hydroxyquinoline (13 mg, 0.087 mmol) and copper iodide (72 mg,0.38 mmol) were added to the suspension. The evacuation/Ar flushingprocess was repeated twice more, and the reaction mixture was heated at130° C. for 18 h under N₂. The mixture was cooled, diluted with 5:1MeOH/NH₄OH (20 mL), and the resulting solution was stirred at ambienttemperature for 30 min. The reaction was further diluted with CH₂Cl₂ (75mL). The resulting solution was filtered through silica gel and thefiltrate was concentrated under reduced pressure. The residue wasdiluted with CH₂Cl₂ and washed with brine (3×20 mL). The organicsolution was dried over Na₂SO₄, filtered and concentrated to dryness.Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2CH₂Cl₂/MeOH/NH₄OH), 100:0 for 5 column volumes, increased to 50:50 over20 column volumes and held for 4 column volumes; increased to 0:100 over10 column volumes and held for 5 column volumes) followed by preparativeHPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H₂O with 0.05%TFA and CH₃CN with 0.05% TFA) gave the title compound (67 mg, 42%) as ayellow film: ¹H NMR (500 MHz, DMSO-d₆) δ 9.19 (s, 1H), 8.50-8.48 (m,1H), 8.05 (d, J=8.0 Hz, 1H), 7.85 (d, J=6.5 Hz, 1H), 7.54-7.51 (m, 2H),7.03-6.99 (m, 2H), 6.78 (dd, J=7.5, 2.0 Hz, 1H), 4.60 (s, 2H), 3.69-3.65(m, 5H), 3.00-2.99 (m, 2H), 1.96-1.90 (m, 2H), 1.36-1.30 (m, 9H); ESI MSm/z 539 [M+H]⁺.

b)1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-onehydrochloride

A solution of tert-butyl6-methyl-8-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-1(2H)-yl)3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(67 mg, 0.13 mmol) in 1.25 M HCl in MeOH (16 mL) was stirred at ambienttemperature for 18 h. The mixture was concentrated to dryness underreduced pressure and diluted with MeOH (2.0 mL) and Et₂O (25 mL). Theresulting solids were collected by filtration and dried to yield thetitle compound (42 mg, 70%) as a yellow powder: mp 274-280° C. decomp;¹H NMR (500 MHz, DMSO-d₆) δ 9.50 (s, 2H), 9.20 (d, J=2.0 Hz, 1H), 8.50(dd, J=8.0, 2.0 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.86 (d, J=7.0 Hz, 1H),7.69 (d, J=8.5 Hz, 1H), 7.59 (d, J=1.5 Hz, 1H), 7.09 (dd, J=8.5, 2.0 Hz,1H), 7.00 (d, J=2.0 Hz, 1H), 6.80 (d, J=7.5, 2.0 Hz, 1H), 4.42-4.41 (m,2H), 3.73 (s, 3H), 3.43-3.41 (m, 2H), 3.11 (t, J=6.0 Hz, 2H), 2.10-2.08(m, 2H); ESI MS m/z 439 [M+H]⁺; HPLC (Method A) 99.0% (AUC), t_(R)=13.7min.

Example 28 Preparation of1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-onehydrochloride a) tert-Butyl6-methyl-8-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

tert-Butyl8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(0.21 g, 0.56 mmol),4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one (0.16 g, 0.68mmol) and Cs₂CO₃ (0.20 g, 0.61 mmol) were suspended in DMSO (2.0 mL),and the air was removed under vacuum for 15 min. The system was flushedwith Ar, and 8-hydroxyquinoline (24 mg, 0.17 mmol) and copper iodide(0.14 g, 0.72 mmol) were added to the suspension. The evacuation/Arflushing process was repeated twice more, and the reaction mixture washeated at 130° C. for 18 h under N₂. The mixture was cooled, dilutedwith 5:1 MeOH/NH₄OH (20 mL), and the resulting solution was stirred atambient temperature for 30 min. The reaction was further diluted withCH₂Cl₂ (75 mL). The resulting solution was filtered through silica geland the filtrate was concentrated under reduced pressure. The residuewas diluted with CH₂Cl₂ and washed with brine (3×20 mL). The organicsolution was dried over Na₂SO₄, filtered and concentrated to dryness.Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2CH₂Cl₂/MeOH/NH₄OH), 100:0 for 5 column volumes, increased to 50:50 over20 column volumes and held for 4 column volumes; increased to 0:100 over10 column volumes and held for 5 column volumes) followed by preparativeHPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H₂O with 0.05%TFA and CH₃CN with 0.05% TFA) gave the title compound (110 mg, 37%) as ayellow film: ¹H NMR (500 MHz, DMSO-d₆) δ 8.70 (d, J=9.0 Hz, 1H), 8.45(d, J=9.0 Hz, 1H), 7.91 (d, J=7.0 Hz, 1H), 7.55-7.54 (m, 2H), 7.37 (d,J=1.5 Hz, 1H), 7.16 (dd, J=7.0, 1.5 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H),4.60 (s, 2H), 3.70-3.66 (m, 5H), 3.01-3.00 (m, 2H), 1.95-1.91 (m, 2H),1.36-1.30 (m, 9H); ESI MS m/z 540 [M+H]⁺.

b)1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-onehydrochloride

A solution of tert-butyl6-methyl-8-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(0.11 g, 0.20 mmol) in 1.25 M HCl in MeOH (25 mL) was stirred at ambienttemperature for 18 h. The mixture was concentrated to dryness anddiluted with MeOH (5.0 mL) and Et₂O (25 mL). The resulting solids werecollected by filtration and dried to provide the title compound (77 mg,80%) as a yellow solid: mp 248-252° C. decomp; ¹H NMR (500 MHz, DMSO-d₆)δ 9.03 (s, 2H), 8.71 (d, J=9.0 Hz, 1H), 8.46 (d, J=8.5 Hz, 1H), 7.91 (d,J=7.0 Hz, 1H), 7.71 (d, J=8.5 Hz, 1H), 7.63 (d, J=2.0 Hz, 1H), 7.38 (d,J=2.0 Hz, 1H), 7.17 (dd, J=7.0, 2.0 Hz, 1H), 7.13 (dd, J=8.5, 1.5 Hz,1H), 4.46-4.45 (m, 2H), 3.75 (s, 3H), 3.46-3.44 (m, 2H), 3.12 (t, J=5.5Hz, 2H), 2.08-2.07 (m, 2H); ESI MS m/z 440 [M+H]⁺; HPLC (Method A) 99.2%(AUC), t_(R)=13.2 min.

Example 29 Preparation of4-(Benzyloxy)-1-(2,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-onehydrochloride a)4-(Benzyloxy)-1-(2,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one

4-(Benzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-onehydrochloride (54 mg, 0.12 mmol) and 37% aqueous formaldehyde (15 μL,0.17 mmol) were dissolved in 1:1 MeOH/CH₂Cl₂ (1.0 mL), and the resultingsolution was stirred at room temperature for 5 min. Sodiumtriacetoxyborohydride (52 mg, 0.25 mmol) was added, and the reactionstirred at room temperature for an additional 45 min. The mixture wasneutralized with saturated NaHCO₃ solution and extracted with CH₂Cl₂(2×10 mL). The combined organic extracts were dried over Na₂SO₄,filtered and concentrated to dryness. Flash chromatography (12 g ISCOCH₂Cl₂/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 2 column volumes to 0:100over 20 column volumes) provided the title compound (24 mg, 46%) as ayellow film: ¹H NMR (300 MHz, CD₃OD) δ 7.60-7.55 (m, 2H), 7.47-7.35 (m,6H), 7.01-6.98 (m, 1H), 6.29-6.26 (m, 1H), 6.11 (d, J=2.7 Hz, 1H), 5.48(s, 2H), 5.17 (s, 2H), 4.16-4.10 (m, 2H), 3.74-3.73 (m, 3H), 3.10-3.06(m, 2H), 2.61 (s, 3H), 2.12-2.06 (m, 2H).

b)4-(Benzyloxy)-1-(2,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-onehydrochloride

1.25 M HCl in MeOH (88 μL) was added to a solution of4-(benzyloxy)-1-(2,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one(23 mg, 0.056 mmol) in MeOH (1.0 mL), and the resulting solution wasstirred at ambient temperature for 1.5 h under N₂. The mixture waspartially concentrated under reduced pressure, diluted with water, andlyophilized to yield the title compound (23 mg, 98%) as a yellow powder;¹H NMR (500 MHz, DMSO-d₆) δ 10.02 (br s, 1H), 7.67 (d, J=8.0 Hz, 1H),7.56 (d, J=7.5 Hz, 1H), 7.49-7.36 (m, 6H), 7.01 (dd, J=8.5, 2.0 Hz, 1H),6.10 (dd, J=7.5, 2.5 Hz, 1H), 5.96 (d, J=2.5 Hz, 1H), 5.15 (s, 2H),4.73-4.71 (m, 1H), 4.52-4.47 (m, 1H), 3.72 (s, 3H), 3.68-3.63 (m, 1H),3.44-3.41 (m, 1H), 3.16-3.03 (m, 2H), 2.81-2.80 (m, 3H), 2.17-2.01 (m,2H); ESI MS m/z 414 [M+H]⁺; HPLC (Method A) 98.3% (AUC), t_(R)=14.3 min.

Example 30 Preparation of4-(Benzyloxy)-1-(2-ethyl-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-onehydrochloride a)4-(Benzyloxy)-1-(2-ethyl-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one

Acetaldehyde (50 μL, 0.88 mmol) and picoline borane complex (47 mg, 0.43mmol) were added to a suspension of4-(benzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-onehydrochloride (64 mg, 0.18 mmol) in 10:1 CH₂Cl₂/AcOH (5.0 mL), and theresulting solution was stirred at ambient temperature for 2 h.Additional acetaldehyde (50 μL, 0.88 mmol) was added to the solution,and the resulting mixture was stirred for 18 h. The mixture wasneutralized with saturated NaHCO₃ solution and extracted with CH₂Cl₂(3×20 mL). The combined organic extracts were dried over Na₂SO₄,filtered and concentrated to dryness. Flash chromatography (12 g ISCOCH₂Cl₂/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 2 column volumes to 0:100over 20 column volumes) provided the title compound (34 mg, 54%) as ayellow solid. ¹H NMR (500 MHz, DMSO-d₆) δ 7.56 (d, J=7.5 Hz, 1H),7.48-7.41 (m, 5H), 7.39-7.37 (m, 1H), 7.35 (d, J=2.0 Hz, 1H), 6.87 (dd,J=8.5, 2.0 Hz, 1H), 6.07 (dd, J=7.5, 3.0 Hz, 1H), 5.96 (d, J=3.0 Hz,1H), 5.14 (s, 2H), 3.88 (s, 2H), 3.66 (s, 3H), 3.03-3.01 (m, 2H), 2.94(t, J=5.5 Hz, 2H), 2.46-2.42 (m, 2H), 1.78-1.76 (m, 2H), 1.01 (t, J=7.0Hz, 3H); ESI MS m/z 428 [M+H]⁺.

b)4-(Benzyloxy)-1-(2-ethyl-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-onehydrochloride

Following the procedure for Example 29 (step b), but substituting4-(benzyloxy)-1-(2-ethyl-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one(33 mg, 0.080 mmol) for4-(benzyloxy)-1-(2,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one,the title compound (33 mg, 91%) was prepared as a yellow solid: ¹H NMR(500 MHz, DMSO-d₆) δ 10.34 (br s, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.56 (d,J=7.5 Hz, 1H), 7.47-7.41 (m, 5H), 7.39-7.35 (m, 1H), 6.99 (dd, J=8.0,1.0 Hz, 1H), 6.09 (dd, J=7.5, 2.5 Hz, 1H), 5.96 (d, J=2.5 Hz, 1H), 5.15(s, 2H), 4.51 (s, 2H), 3.71 (s, 3H), 3.47-3.44 (m, 2H), 3.09-3.08 (m,2H), 2.97-2.95 (m, 2H), 2.08-2.05 (m, 2H), 1.22 (t, J=6.5 Hz, 3H); ESIMS m/z 428 [M+H]⁺; HPLC (Method A) 98.8% (AUC), t_(R)=15.2 min.

Example 31 Preparation of4-(Benzyloxy)-1-(2-isopropyl-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-onehydrochloride a)4-(Benzyloxy)-1-(2-isopropyl-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-onehydrochloride

Acetone (2.81 mL) and picoline borane complex (59 mg, 0.55 mmol) wereadded to a suspension of4-(benzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-onehydrochloride (80 mg, 0.18 mmol) in 10:1 CH₂Cl₂/AcOH (3.1 mL) and theresulting solution was stirred at reflux for 18 h. Acetone (1.0 mL) andpicoline borane complex (50 mg, 0.46 mmol) were added to the solutionand the resulting mixture was stirred for 48 h. The mixture waspartitioned with H₂O (5 mL) and CH₂Cl₂ (20 mL) and extracted with CH₂Cl₂(2×20 mL). The combined organic extracts were dried over Na₂SO₄,filtered and concentrated to dryness under reduced pressure. Flashchromatography (12 g ISCO CH₂Cl₂/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for2 column volumes to 0:100 over 20 column volumes) followed bypreparative TLC (Analtech, 20×20 cm, 1000 microns, 50:50 (1:1hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH) provided a white solid thatupon concentration with 1.25 M HCl in MeOH (2.0 mL) afforded the titlecompound (33 mg, 38%) as an off-white solid: ¹H NMR (500 MHz, DMSO-d₆) δ9.92 (br s, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.57 (d, J=7.5 Hz, 1H),7.50-7.35 (m, 6H), 7.02 (dd, J=8.0, 1.5 Hz, 1H), 6.10 (dd, J=7.5, 2.5Hz, 1H), 5.97 (d, J=3.0 Hz, 1H), 5.15 (s, 2H), 4.65-4.53 (m, 2H), 3.72(s, 3H), 3.57-3.47 (m, 3H), 3.11 (t, J=6.0 Hz, 2H), 2.24-2.07 (m, 2H),1.34-1.30 (m, 6H); ESI MS m/z 442 [M+H]⁺; HPLC (Method A, 223 nm) 98.4%(AUC), t_(R)=15.7 min.

Example 32 Preparation of1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(4-(methylthio)phenyl)pyridin-2(1H)-onehydrochloride a) 4-(4-(Methylthio)phenyl)pyridin-2(1H)-one (CAS RegistryNumber 1173157-45-3) (WO 2009/089482 to Guzzo et al., which is herebyincorporated by reference in its entirety)

A suspension of 4-bromo-2-methoxypyridine (1.225 g, 6.511 mmol),4-methylthiophenyl boronic acid (2.188 g, 13.02 mmol), PdCl₂(dppf) (531mg, 0.651 mmol), and K₂CO₃ (1.797 g, 13.02 mmol) in DMSO (10 mL) wasdegassed under reduced pressure for 25 min. The suspension was put underN₂ and stirred at 95° C. for 16 h. The suspension was cooled, H₂O wasadded, and the suspension was filtered to afford a light colored solid.Flash chromatography (silica gel, hexanes/(1:1 EtOAc/hexanes), 100:0 to0:100) afforded 1.10 g of a white powder. The white powder was dilutedwith concentrated HCl solution (50 mL) and stirred at reflux for 24 h.The reaction was cooled and concentrated under reduced pressure. Theresidue was neutralized with saturated NaHCO₃ solution, and the solidwas collected by filtration. The solid was washed with H₂O to afford thetitle compound (1.103 g, 71%) as a tan solid: ¹H NMR (300 MHz, DMSO-d₆)δ 7.65 (d, J=8.4 Hz, 2H), 7.43 (d, J=6.9 Hz, 1H), 7.34 (d, J=8.4 Hz,2H), 6.57 (d, J=1.7 Hz, 1H), 6.50 (dd, J=6.9, 1.7 Hz, 1H), 3.34 (s, 3H).

b) tert-Butyl6-methyl-8-(4-4-(methylthio)phenyl)-2-oxopyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

tert-Butyl8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(0.15 g, 0.39 mmol), 4-(4-(methylthio)phenyl)pyridin-2(1H)-one (0.11 g,0.52 mmol) and Cs₂CO₃ (0.14 g, 0.44 mmol) were suspended in DMSO (2.4mL), and the air was removed under vacuum for 15 min. The system wasflushed with Ar, and 8-hydroxyquinoline (17 mg, 0.12 mmol) and copperiodide (98 mg, 0.52 mmol) were added to the suspension. Theevacuation/Ar flushing process was repeated twice more, and the reactionmixture was heated at 130° C. for 18 h under N₂. The mixture was cooled,diluted with (5.0:3.5:1.5) NH₄Cl(aq.)/NH₄OH/H₂O (30 mL), and theresulting suspension was stirred at ambient temperature for 30 min. Theresulting solids were collected by filtration, dissolved in CH₂Cl₂ (20mL), and the resulting solution was washed with (5.0:3.5:1.5)NH₄Cl(aq.)/NH₄OH/H₂O (2×20 mL). The organic solution was dried overNa₂SO₄, filtered and concentrated to dryness under reduced pressure.Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2CH₂Cl₂/MeOH/NH₄OH), 100:0 for 2 column volumes, increased to 50:50 over20 column volumes and held for 4 column volumes; increased to 0:100 over10 column volumes) followed by trituration with MeOH and hot Et₂Oprovided the title compound (54 mg, 26%) as an off-white powder: ¹H NMR(500 MHz, DMSO-d₆) δ 7.75-7.71 (m, 3H), 7.52-7.48 (m, 2H), 7.38 (d,J=8.5 Hz, 1H), 7.01 (d, J=8.5 Hz, 1H), 6.76 (d, J=2.0 Hz, 1H), 6.66 (d,J=7.0 Hz, 1H), 4.60 (s, 2H), 3.68-3.65 (m, 5H), 3.01-2.99 (m, 3H), 2.53(s, 3H), 1.94-1.90 (m, 2H), 1.36-1.29 (m, 9H).

c)1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(4-(methylthio)phenyl)pyridin-2(1H)-onehydrochloride

tert-Butyl6-methyl-8-(4-4-(methylthio)phenyl)-2-oxopyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(54 mg, 0.10 mmol) was treated with 1.25 M HCl in MeOH (6.0 mL), and theresulting solution was stirred at ambient temperature for 18 h. Thesolution was partially concentrated under reduced pressure and dilutedwith Et₂O. The resulting solids were collected by filtration and washedwith CH₂Cl₂ to provide the title compound (26 mg, 60%) as a brownpowder: mp 250-255° C. decomp.; ¹H NMR (500 MHz, DMSO-d₆) δ 8.98 (br s,2H), 7.75-7.67 (m, 4H), 7.58 (s, 1H), 7.38 (d, J=8.0 Hz, 2H), 7.09 (d,J=8.5 Hz, 1H), 6.76 (s, 1H), 6.68 (d, J=7.0 Hz, 1H), 4.45 (s, 2H), 3.74(s, 3H), 3.46-3.45 (m, 2H), 3.12-3.10 (m, 2H), 2.54 (s, 3H), 2.07-2.05(m, 2H); ESI MS m/z 416 [M+H]⁺; HPLC (Method A) 97.1% (AUC), t_(R)=14.5min.

Example 33 Preparation of1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(6-methylpyridin-3-yl)pyridin-2(1H)-onehydrochloride a) tert-Butyl6-methyl-8-(4-(6-methylpyridin-3-yl)-2-oxopyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

tert-Butyl8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(0.17 g, 0.44 mmol), 4-(6-(methyl)pyridin-3-yl)pyridin-2(1H)-one (90 mg,0.48 mmol) and Cs₂CO₃ (0.14 g, 0.44 mmol) were suspended in DMSO (2.5mL), and the air was removed under vacuum for 15 min. The system wasflushed with Ar, and 8-hydroxyquinoline (19 mg, 0.13 mmol) and copperiodide (0.12 g, 0.66 mmol) were added to the suspension. Theevacuation/Ar flushing process was repeated twice more, and the reactionmixture was heated at 130° C. for 18 h under N₂. The mixture was cooled,diluted with (5.0:3.5:1.5) NH₄Cl(aq.)/NH₄OH/H₂O (30 mL), and theresulting suspension was stirred at ambient temperature for 30 min. Theresulting solids were collected by filtration, dissolved in CH₂Cl₂ (20mL), and the resulting solution was washed with (5.0:3.5:1.5)NH₄Cl(aq.)/NH₄OH/H₂O (2×20 mL). The resulting organic solution was driedover Na₂SO₄, filtered and concentrated to dryness under reducedpressure. Flash chromatography (12 g ISCO column, (1:1hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 2 column volumes,increased to 50:50 over 20 column volumes and held for 4 column volumes;increased to 0:100 over 10 column volumes) followed by preparative HPLC(Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H₂O with 0.05% TFAand CH₃CN with 0.05% TFA) gave the title compound (53 mg, 25%) as ayellow film: ¹H NMR (500 MHz, DMSO-d₆) δ 8.87 (s, 1H), 8.10-8.08 (m,1H), 7.76 (d, J=6.5 Hz, 1H), 7.52 (d, J=7.0 Hz, 1H), 7.49 (s, 1H), 7.40(d, J=8.0 Hz, 1H), 7.03-7.01 (m, 1H), 6.84 (s, 1H), 6.71 (d, J=7.0 Hz,1H), 4.60 (s, 2H), 3.77-3.66 (m, 5H), 3.01-2.99 (m, 2H), 2.54 (s, 3H),1.99-1.86 (m, 2H), 1.36-1.30 (m, 9H).

b)1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(6-methylpyridin-3-yl)pyridin-2(1H)-onehydrochloride

tert-Butyl6-methyl-8-(4-(6-methylpyridin-3-yl)-2-oxopyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(50 mg, 0.10 mmol) was treated with 1.25 M HCl in MeOH (6.0 mL), and theresulting solution was stirred at ambient temperature for 36 h. Thesolution was partially concentrated under reduced pressure and dilutedwith Et₂O. The resulting solids were collected by filtration and washedwith 99:1 CH₂Cl₂/MeOH to provide the title compound (37 mg, 85%) as atan solid: mp 245-250° C. decomp.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.10 (brs, 2H), 9.04 (s, 1H), 8.44 (s, 1H), 7.82 (d, J=7.0 Hz, 1H), 7.70-7.68(m, 2H), 7.58 (s, 1H), 7.09 (d, J=8.0 Hz, 1H), 6.96 (s, 1H), 6.79 (d,J=7.0 Hz, 1H), 4.45. (s, 2H), 3.74 (s, 3H), 3.45-3.44 (m, 2H), 3.11-3.09(m, 2H), 2.66 (s, 3H), 2.08-2.07 (m, 2H); ESI MS m/z 385 [M+H]⁺; HPLC(Method A) 97.9% (AUC), t_(R)=8.9 min.

Example 34 Preparation of1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-((6-methylpyridin-3-yl)methoxy)pyridin-2(1H)-onehydrochloride a) 2-Chloro-4-((6-methylpyridin-3-yl)methoxy)pyridine

(6-Methylpyridin-3-yl)methanol (3.25 g, 26.4 mmol),2-chloro-4-iodopyridine (5.7 g, 24 mmol), cesium carbonate (10.1 g, 31.2mmol), CuI (0.90 g, 4.8 mmol) and 1,10-phenanthroline (0.86 g, 4.8 mmol)were stirred in toluene (15 mL) and degassed with a nitrogen stream for10 minutes. The mixture was heated to 105° C. for 16 h, allowed cool andfiltered through a silica plug eluting with ethyl acetate. The filtratewas concentrated, and the residue was purified by column chromatography(80 g ISCO column column eluting with ethyl acetate/hexanes; gradient100% hexanes to 100% ethyl acetate) to provide the title compound (4.2g, 75%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 8.54 (d, J=2.0 Hz,1H), 8.21 (d, J=5.7 Hz, 1H), 7.65-7.62 (dd, J=7.9, 2.2 Hz, 1H), 7.21 (d,J=7.9 Hz, 1H), 6.91 (d, J=2.2 Hz, 1H), 6.83-6.80 (dd, J=5.8, 2.2 Hz,1H), 5.08 (s, 2H), 2.59 (s, 3H).

b) 4-((6-Methylpyridin-3-yl)methoxy)pyridin-2(1H)-one

2-Chloro-4-((6-methylpyridin-3-yl)methoxy)pyridine (4.20 g, 17.9 mmol)and ammonium acetate (6.91 g, 89.7 mmol) were heated at 110° C. in amixture of formic acid (20 mL) and water (20 mL) for 5 days. The mixturewas concentrated to remove most of the liquid and then adjusted to pH 8with NaHCO₃ solution. The solid was filtered off to provide the titlecompound (3.0 g, 77%) as a white solid: ¹H NMR (300 MHz, DMSO-d₆) δ11.27-11.04 (br s, 1H), 8.51 (s, 1H), 7.73 (d, J=7.1 Hz, 1H), 7.29-7.24(m, 2H), 5.89 (d, J=7.2 Hz, 1H), 5.82 (s, 1H), 5.05 (s, 2H), 2.50 (s,3H).

c) tert-Butyl 6-methyl-8-(4-((6-methylpyridine-3-yl)methoxy)-2-oxopyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

tert-Butyl8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(0.15 g, 0.39 mmol), 4-((6-methylpyridin-3-yl)methoxy)pyridin-2(1H)-one(90 mg, 0.46 mmol) and Cs₂CO₃ (0.14 g, 0.44 mmol) were suspended in DMSO(2.4 mL), and the air was removed under vacuum for 15 min. The systemwas flushed with Ar, and 8-hydroxyquinoline (17 mg, 0.12 mmol) andcopper iodide (0.11 g, 0.60 mmol) were added to the suspension. Theevacuation/Ar flushing process was repeated twice more, and the reactionmixture was heated at 130° C. for 18 h under N₂. The mixture was cooled,diluted with (5.0:3.5:1.5) NH₄Cl(aq.)/NH₄OH/H₂O (30 mL), and theresulting suspension was stirred at ambient temperature for 30 min. Theresulting solids were collected by filtration, dissolved in CH₂Cl₂ (20mL) and washed with (5.0:3.5:1.5) NH₄Cl(aq.)/NH₄OH/H₂O (2×20 mL). Theresulting organic solution was dried over Na₂SO₄, filtered andconcentrated to dryness under reduced pressure. Flash chromatography (12g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0for 4 column volumes, increased to 50:50 over 20 column volumes and heldfor 4 column volumes; increased to 0:100 over 10 column volumes and heldfor 20 column volumes) gave the title compound (0.12 g, 57%) as a yellowfilm: ¹H NMR (500 MHz, DMSO-d₆) δ 8.55 (d, J=2.0 Hz, 1H), 7.77 (dd,J=8.0, 2.5 Hz, 1H), 7.55 (d, J=7.0 Hz, 1H), 7.47 (d, J=9.0 Hz, 1H), 7.38(s, 1H), 7.31 (d, J=8.0 Hz, 1H), 6.93-6.91 (m, 1H), 6.07-6.06 (m, 1H),5.99 (d, J=3.0 Hz, 1H), 5.15 (s, 2H), 4.58 (s, 2H), 3.66-3.64 (m, 5H),2.99-2.97 (m, 2H), 2.50 (s, 3H), 1.93-1.89 (m, 2H), 1.35-1.28 (m, 9H).

d)1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-((6-methylpyridin-3-yl)methoxy)pyridin-2(1H)-onehydrochloride

tert-Butyl 6-methyl-8-(4-((6-methylpyridine-3-yl)methoxy)-2-oxopyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(0.12 g, 0.22 mmol) was treated with 1.25 M HCl in MeOH (13 mL), and theresulting solution was stirred at ambient temperature for 18 h. Thesolution was concentrated to dryness to provide the title compound (0.10g, quantitative) as a brown solid: ¹H NMR (500 MHz, DMSO-d₆) δ 9.17 (s,2H), 8.89 (s, 1H), 8.51 (d, J=8.0 Hz, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.65(d, J=8.5 Hz, 1H), 7.61 (d, J=7.5 Hz, 1H), 7.47 (d, J=1.5 Hz, 1H), 6.98(dd, J=8.5, 1.5 Hz, 1H), 6.14 (dd, J=8.0, 2.5 Hz, 1H), 6.03 (d, J=2.0Hz, 1H), 5.33 (s, 2H), 4.44-4.41 (m, 2H), 3.71 (s, 3H), 3.44-3.42 (m,2H), 3.10-3.08 (m, 2H), 2.76 (s, 3H), 2.08-2.04 (m, 2H); ESI MS m/z 415[M+H]⁺; HPLC (Method A) >99% (AUC), t_(R)=9.4 min.

Example 35 Preparation of4-(Benzyloxy)-1-(1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-onehydrochloride a) 7-Bromo-2,3-dihydro-1H-carbazol-4(9H)-one oxime

Hydroxylamine hydrochloride (0.85 g, 12 mmol) and sodium acetate (1.0 g,12 mmol) were added to a suspension of7-bromo-2,3-dihydro-1H-carbazol-4(9H)-one oxime (3.0 g, 8.2 mmol) inEtOH (22 mL) and H₂O (7.3 mL), and the resulting suspension was heatedat reflux for 6 h. The suspension was cooled and stirred at ambienttemperature for 48 h. Additional hydroxylamine hydrochloride (0.43 g,6.1 mmol) and sodium acetate (0.50 g, 6.1 mmol) were added to thesuspension, and the resulting suspension was heated at reflux for 6 h.Hydroxylamine hydrochloride (0.43 g, 6.1 mmol) and sodium acetate (0.57g, 6.9 mmol) were added to the suspension for a third time, and thesuspension was heated at reflux for 18 h. The reaction was cooled andthe suspension was concentrated under reduced pressure. The resultingsolids were triturated in hot CH₂Cl₂ (100 mL) to provide the titlecompound (3.44 g, quant.) as a light yellow solid: ¹H NMR (500 MHz,DMSO-d₆) δ 11.42 (s, 1H), 10.31 (s, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.48(d, J=1.5 Hz, 1H), 7.16 (dd, J=8.5, 1.5 Hz, 1H), 2.78 (t, J=6.5 Hz, 2H),2.66 (t, J=6.5 Hz, 2H), 1.93-1.88 (m, 2H).

b) 8-Bromo-2,3,4,5-tetrahydroazepino[4,3-b]indol-1(6H)-one

A suspension of 7-bromo-2,3-dihydro-1H-carbazol-4(9H)-one oxime (1.9 g,5.1 mmol) in PPA (36 g) was mechanically rotated in a water bath set at100° C. for 4.5 h. The mixture was placed in an ice bath and slowlyquenched with H₂O (100 mL). The resulting solids were isolated byfiltration. The solids were washed with water, 1N NaOH (50 mL) and H₂O(100 mL) and dried to afford the title compound (1.2 g, 60%) as a lightpink powder: ¹H NMR (500 MHz, DMSO-d₆) δ 11.56 (s, 1H), 8.12 (d, J=8.5Hz, 1H), 7.47-7.45 (m, 2H), 7.15 (dd, J=8.5, 2.0 Hz, 1H), 3.22-3.19 (m,2H), 3.09 (t, J=7.0 Hz, 2H), 2.01-1.97 (m, 2H).

c) tert-Butyl8-bromo-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

BH₃.THF (1.0 M solution in THF, 53 mL) was slowly added to a solution of8-bromo-2,3,4,5-tetrahydroazepino[4,3-b]indol-1(6H)-one (1.1 g, 3.9mmol) in THF (66 mL), and the resulting solution was heated at refluxfor 48 h. The reaction was cooled to 50° C., additional BH₃.THF (1.0 Msolution in THF, 10 mL) was added, and the resulting solution was heatedat reflux for 48 h. The reaction was cooled to 50° C., BH₃.THF (1.0 Msolution in THF, 10 mL) was added, and the resulting solution was heatedto reflux for 18 h. The reaction was cooled to 50° C., BH₃.THF (1.0 Msolution in THF, 10 mL) was added for the fourth time, and the resultingsolution was heated to reflux for 18 h. The reaction was cooled, andAcOH was added slowly until gas evolution ceased. The resulting solutionwas concentrated under reduced pressure, and the resulting solids weredissolved in toluene (60 mL) and 12 N HCl (9 mL) and heated at refluxfor 2 h. The solution was cooled, partitioned with H₂O (200 mL) and theresulting layers separated. The aqueous phase was made basic with 6 NNaOH, and the resulting solids were collected by filtration. The solidswere diluted with 1.2:1 H₂O/i-PrOH (14 mL) under N₂. K₂CO₃ (0.61 g, 4.4mmol) and Boc₂O (0.97 g, 4.4 mmol) were added to the solution, and theresulting solution was stirred at ambient temperature for 18 h. Thesolution was diluted with H₂O (10 mL), and the resulting solids werecollected by filtration. Flash chromatography (80 g ISCO hexanes/EtOAc,90:10 held to 2 column volumes, increase to 50:50 over 12 column volumesand held for 5 column volumes) provided the title compound (0.76 g, 54%)as an off-white film: ¹H NMR (500 MHz, DMSO-d₆) δ 11.03-11.02 (d, J=10.5Hz, 1H), 7.41 (d, J=1.5 Hz, 1H), 7.35 (d, J=8.5 Hz, 1H), 7.08 (dd,J=8.5, 1.5 Hz, 1H), 4.51-4.49 (d, J=11.0 Hz, 2H), 3.62 (t, J=5.5 Hz,2H), 2.90 (t, J=5.5 Hz, 2H), 1.83-1.78 (m, 2H), 1.35-1.23 (m, 9H).

d) tert-Butyl8-bromo-6-tosyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

6 N NaOH (10 mL), TsCl (0.48 g, 2.5 mmol) and (Bu₄NH)₂SO₄ (50% solutionin water, 0.17 mL) were added to a solution of tert-butyl8-bromo-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (0.76g, 2.1 mmol) in toluene (17 mL), and the resulting solution was stirredfor 18 h. Additional TsCl (55 mg, 0.29 mmol) was added, and the reactionwas stirred for 18 h. The solution was partitioned with H₂O and theresulting layers were separated. The aqueous phase was extracted withEtOAc (2×20 mL). The combined organic extracts were washed with brine(25 mL), dried over Na₂SO₄ and concentrated to dryness under reducedpressure. Flash chromatography (40 g ISCO hexanes/EtOAC, 90:10 for 2column volumes, increased to 50:50 over 12 column volumes and held for 4column volumes) provided the title compound (0.54 g, 50%) as a whitefoam: ¹H NMR (500 MHz, DMSO-d₆) δ 8.24-8.20 (m, 1H), 7.64 (d, J=8.0 Hz,2H), 7.51 (d, J=8.5 Hz, 1H), 7.46 (dd, J=8.5, 1.5 Hz, 1H), 7.37 (d,J=8.0 Hz, 2H) 4.44-4.40 (m, 2H), 3.56 (t, J=5.5 Hz, 2H), 3.20-3.18 (m,2H), 2.31 (s, 3H), 1.86-1.84 (m, 2H), 1.29-1.03 (m, 9H).

e) tert-Butyl8-(4-benzyloxy)-2-oxopyridin-1(2H)-yl)-6-tosyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1)-carboxylate

tert-Butyl8-bromo-6-tosyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(0.20 g, 0.39 mmol), 4-benzyloxy pyridinone (0.10 g, 0.51 mmol) andCs₂CO₃ (0.14 g, 0.43 mmol) were suspended in DMSO (2.3 mL), and the airwas removed under vacuum for 15 min. The system was flushed with Ar, and8-hydroxyquinoline (17 mg, 0.12 mmol) and copper iodide (96 mg, 0.51mmol) were added to the suspension. The evacuation/Ar flushing processwas repeated twice more, and the reaction mixture was heated at 130° C.for 18 h under N₂. The mixture was cooled, diluted with 5:1 MeOH/NH₄OH(15 mL), and the resulting solution was stirred at ambient temperaturefor 30 min. The solution was further diluted with CH₂Cl₂ (50 mL). Theresulting solution was filtered through silica gel, and the filtrate wasconcentrated under reduced pressure. The residue was diluted with CH₂Cl₂and washed with brine (2×25 mL). The organic solution was dried overNa₂SO₄, filtered and concentrated to dryness. Flash chromatography (12 gISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for5 column volumes, increased to 50:50 over 20 column volumes and held for5 column volumes; increase to 0:100 over 10 column volumes) gave thetitle compound (0.14 g, 57%) as a yellow film: ¹H NMR (300 MHz CDCl₃) δ8.26-8.21 (m, 1H), 7.65 (d, J=8.1 Hz, 2H), 7.44-7.20 (m, 10H), 6.10-6.08(m, 2H), 5.07 (s, 2H), 4.55-4.46 (m, 2H), 3.67-3.60 (m, 2H), 3.29-3.26(m, 2H), 2.33 (s, 3H), 1.95-1.94 (m, 2H), 1.40-1.23 (m, 9H).

f) tert-Butyl8-(4-benzyloxy)-2-oxopyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

NaOH (0.44 g, 11 mmol) was added to a solution of tert-butyl8-(4-benzyloxy)-2-oxopyridin-1(2H)-yl)-6-tosyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(0.14 g, 0.22 mmol) in 1:1 CH₂Cl₂/MeOH (20 mL), and the resultingsolution was heated at reflux for 18 h. The mixture was diluted with H₂Oand was extracted with CH₂Cl₂ (3×20 mL). The combined organic extractswere dried over Na₂SO₄ and concentrated under reduced pressure todryness. Flash chromatography (12 g ISCO column, CH₂Cl₂/(80:18:2CH₂Cl₂/MeOH/NH₄OH), 100:0 for 5 column volumes, increased to 25:75 over20 column volumes and held for 2 column volumes) provided the titlecompound (58 mg, 55%) as a yellow film: ¹H NMR (500 MHz, DMSO-d₆) δ11.08-11.05 (m, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.48-7.35 (m, 6H), 7.19 (s,1H), 6.87 (d, J=8.0 Hz, 1H), 6.06 (dd, J=7.0, 2.0 Hz, 1H), 5.95 (d,J=2.5 Hz, 1H), 5.14 (s, 2H), 4.55 (s, 2H), 3.65 (t, J=5.0 Hz, 2H), 2.94(t, J=5.5 Hz, 2H), 1.83-1.80 (m, 2H), 1.35-1.28 (m, 9H).

h)4-(Benzyloxy)-1-(1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-onehydrochloride

tert-Butyl8-(4-benzyloxy)-2-oxopyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(55 mg, 0.11 mmol) was treated with 1.25 M HCl in MeOH (11 mL), and theresulting solution was stirred at ambient temperature for 18 h. Thesolution was concentrated to dryness under reduced pressure. PreparativeTLC (Analtech, 20×20 cm, 1000 microns, 80:18:2 CH₂Cl₂/MeOH/NH₄OH)provided an off-white solid, and the resulting solid was treated with1.25 M HCl in MeOH (1.0 mL). The resulting solution was concentrated toprovide the title compound (22 mg, 50%) as an off-white solid: ¹H NMR(500 MHz, DMSO-d₆) δ 11.45 (s, 1H), 8.90 (s, 2H), 7.61 (d, J=8.5 Hz,1H), 7.54 (d, J=7.5 Hz, 1H), 7.48-7.36 (m, 5H), 7.28 (d, J=2.0 Hz, 1H),6.95 (dd, J=8.0, 2.0 Hz, 1H), 6.08 (dd, J=7.5, 3.0 Hz, 1H), 5.95 (d,J=2.5 Hz, 1H), 5.14 (s, 2H), 4.42-4.41 (m, 2H), 3.47-3.45 (s, 2H), 3.03(t, J=5.0 Hz, 2H), 2.01-1.99 (m, 2H); ESI MS m/z 386 [M+H]⁺; HPLC(Method A) 97.5% (AUC), t_(R)=14.3 min.

Example 36 Preparation of1-(1,2,3,4,5,6-Hexahydroazepino[4,3-b]indol-8-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-onehydrochloride a) tert-Butyl8-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-6-tosyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

tert-Butyl8-bromo-6-tosyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(0.20 g, 0.39 mmol),4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (0.10 g, 0.43 mmol)and Cs₂CO₃ (0.14 g, 0.43 mmol) were suspended in DMSO (2.3 mL), and theair was removed under vacuum for 15 min. The system was flushed with Ar,and 8-hydroxyquinoline (17 mg, 0.12 mmol) and copper iodide (985 mg,0.50 mmol) were added to the suspension. The evacuation/Ar flushingprocess was repeated twice more, and the reaction mixture was heated at130° C. for 18 h under N₂. The solution was cooled, diluted with 5:1MeOH/NH₄OH (15 mL), and the resulting solution was stirred at ambienttemperature for 30 min. The reaction was further diluted with CH₂Cl₂ (50mL). The resulting solution was filtered through silica gel, and thefiltrate was concentrated under reduced pressure. The residue wasdiluted with CH₂Cl₂ and washed with brine (3×25 mL). The organicsolution was dried over Na₂SO₄, filtered and concentrated to dryness.Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2CH₂Cl₂/MeOH/NH₄OH), 100:0 for 5 column volumes, increased to 50:50 over20 column volumes and held for 5 column volumes; increased to 0:100 over10 column volumes and held for 8 column volumes) gave the title compound(98 mg, 37%) as a yellow film: ¹H NMR (300 MHz, DMSO-d₆) δ 9.16 (s, 1H),8.40-8.38 (m, 2H), 8.23-8.18 (m, 1H), 7.93 (d, J=7.2 Hz, 1H), 7.75-7.65(m, 3H), 7.39-7.33 (m, 4H), 7.12 (dd, J=7.2, 1.8 Hz, 1H), 4.48 (s, 2H),3.61-3.60 (m, 2H), 3.33-3.27 (m, 2H), 2.31 (s, 3H), 1.89-1.88 (m, 2H),1.30-1.08 (m, 9H).

b) tert-Butyl8-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1)-carboxylate

NaOH (0.28 g, 7.1 mmol) was added to a solution of tert-butyl8-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-6-tosyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(96 mg, 0.14 mmol) in 1:1 CH₂Cl₂/MeOH (22 mL), and the resultingsolution was heated at reflux for 18 h. The mixture was diluted with H₂Oand extracted with CH₂Cl₂ (3×20 mL). The organic extracts wereconcentrated and partitioned with H₂O and EtOAc. The aqueous layer wasextracted with EtOAc (3×20 mL). The combined organic extracts werewashed with brine (25 mL), dried over Na₂SO₄, filtered and concentratedto dryness under reduced pressure. Flash chromatography (12 g ISCOcolumn, CH₂Cl₂/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 5 column volumes,increased to 25:75 over 20 column volumes and held for 8 column volumes)followed by flash chromatography (12 g, ISCO column, Et₂O/(9:1MeOH/NH₄OH), 100:0 increase to 50:50 over 120 column volumes, increasedto 0:100 over 90 column volumes) provided the title compound (32 mg,43%) as a yellow powder: ¹H NMR (500 MHz, DMSO-d₆) δ 11.15-11.12 (m,1H), 9.14 (s, 1H), 8.39-8.32 (m, 2H), 7.82 (d, J=6.0 Hz, 1H), 7.50 (d,J=8.0 Hz, 1H), 7.32 (s, 1H), 7.26 (d, J=2.0 Hz, 1H), 7.04 (dd, J=7.0,1.5 Hz, 1H), 7.00-6.98 (m, 1H), 4.57 (s, 2H), 3.66 (t, J=5.5 Hz, 2H),2.96 (t, J=6.0 Hz, 2H), 1.85-1.81 (m, 2H), 1.36-1.29 (m, 9H).

c)1-(1,2,3,4,5,6-Hexahydroazepino[4,3-b]indol-8-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-onehydrochloride

tert-Butyl8-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(30 mg, 0.057 mmol) was treated with 1.25 M HCl in MeOH (5.5 mL), andthe resulting solution was stirred at ambient temperature for 18 h. Thesolution was partially concentrated and diluted with Et₂O. The resultingsolids were collected by filtration, washed with Et₂O and dried to yieldthe title compound (13 mg, 51%) as a yellow powder: mp 310-320° C.decomp.; ¹H NMR (500 MHz, DMSO-d₆) δ 11.51 (s, 1H), 9.14 (s, 1H), 8.81(s, 2H), 8.39 (dd, J=8.5, 2.0 Hz, 1H), 8.34 (d, J=8.5 Hz, 1H), 7.82 (d,J=7.5 Hz, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.41 (d, J=2.0 Hz, 1H), 7.26 (d,J=2.0 Hz, 1H), 7.08-7.04 (m, 2H), 4.44 (s, 2H), 3.49-3.47 (m, 2H),3.06-3.04 (m, 2H), 2.03-2.01 (m, 2H); ESI MS m/z 425 [M+H]⁺; HPLC(Method A) 96.9% (AUC), t_(R)=13.7 min.

Example 37 Preparation of1-(1,2,3,4,5,6-Hexahydroazepino[4,3-b]indol-8-yl)-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-onehydrochloride a) tert-Butyl8-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-6-tosyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1)-carboxylate

tert-Butyl8-bromo-6-tosyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(0.20 g, 0.39 mmol),4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one (0.10 g, 0.43mmol), and Cs₂CO₃ (0.14 g, 0.43 mmol) were suspended in DMSO (2.3 mL),and the air was removed under vacuum for 15 min. The system was flushedwith Ar, and 8-hydroxyquinoline (17 mg, 0.12 mmol) and copper iodide (95mg, 0.50 mmol) were added to the suspension. The evacuation/Ar flushingprocess was repeated twice more, and the reaction mixture was heated at130° C. for 18 h under N₂. The mixture was cooled, diluted with 5:1MeOH/NH₄OH (15 mL), and the resulting solution was stirred at ambienttemperature for 30 min. The reaction was further diluted with CH₂Cl₂ (75mL), the resulting solution was filtered through silica gel, and thefiltrate was concentrated under reduced pressure. The residue wasdiluted with CH₂Cl₂ and washed with brine (3×25 mL). The organicsolution was dried over Na₂SO₄, filtered and concentrated to drynessunder reduced pressure. Flash chromatography (12 g ISCO column, (1:1hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 5 column volumes,increased to 50:50 over 20 column volumes and held for 4 column volumes;increased to 0:100 over 10 column volumes and held for 12 columnvolumes) gave tert-butyl8-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(40 mg, 19%) and the title compound (59 mg, 22%) as a yellow film.

Data for tert-Butyl8-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate:¹H NMR (500 MHz, DMSO-d₆) δ 11.17-11.14 (m 1H), 8.69 (d, J=8.5 Hz, 1H),8.45 (d, J=9.0 Hz, 1H), 7.90 (d, J=7.0 Hz, 1H), 7.36 (d, J=1.5 Hz, 1H),7.35 (s, 1H), 7.14 (dd, J=7.5, 2.0 Hz, 1H), 7.01 (d, J=8.0 Hz, 2H), 4.58(s, 2H), 3.66 (t, J=5.5 Hz, 2H), 2.96 (t, J=5.5 Hz, 2H), 1.86-1.82 (m,2H),1.36-1.30 (m, 9H).

Data for title compound: ¹H NMR (500 MHz, DMSO-d₆) δ 8.72 (d, J=9.0 Hz,1H), 8.47 (d, J=9.0 Hz, 1H), 8.25-8.20 (m, 1H), 8.00 (d, J=6.5 Hz, 1H),7.75-7.66 (m, 3H), 7.42-7.34 (m, 4H), 7.21 (d, J=8.5 Hz, 1H), 4.49-4.48(m, 2H), 3.60 (t, J=5.5 Hz, 2H), 2.27 (t, J=5.0 Hz, 2H), 2.31 (s,3H),1.90-1.88 (m, 2H), 1.30-1.09 (m, 9H); ESI MS m/z 680 [M+H]⁺.

h) tert-Butyl8-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1)-carboxylate

NaOH (0.17 g, 4.3 mmol) was added to a solution of tert-butyl8-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-6-tosyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(59 mg, 0.084 mmol) and tert-butyl8-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(40 mg, 0.076 mmol) in 1:1 CH₂Cl₂/MeOH (13 mL) and the resultingsolution was heated at reflux for 24 h. The mixture was diluted with H₂O(10 mL) and extracted with CH₂Cl₂ (3×20 mL). The combined organicextracts were washed with brine (25 mL), dried over Na₂SO₄, filtered andconcentrated to dryness under reduced pressure. Flash chromatography (12g ISCO column, CH₂Cl₂/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 5 columnvolumes, increased to 25:75 over 20 column volumes and held for 8 columnvolumes) provided the title compound (55 mg, 63%) as a yellow film: ¹HNMR (500 MHz, DMSO-d₆) δ 11.17-11.14 (m, 1H), 8.69 (d, J=9.0 Hz, 1H),8.45 (d, J=9.0 Hz, 1H), 7.90 (d, J=7.0 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H),7.36 (d, J=2.0 Hz, 1H), 7.34 (s, 1H), 7.14 (dd, J=7.0, 2.0 Hz, 1H), 7.01(d, J=8.0 Hz, 1H), 4.58 (s, 2H), 3.66 (t, J=5.0 Hz, 2H), 2.96 (t, J=5.5Hz, 2H), 1.85-1.82 (m, 2H), 1.36-1.30 (m, 9H).

b)1-(1,2,3,4,5,6-Hexahydroazepino[4,3-b]indol-8-yl)-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-onehydrochloride

tert-Butyl8-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(54 mg, 0.10 mmol) was treated with 1.25 M HCl in MeOH (9.9 mL), and theresulting solution was stirred at ambient temperature for 18 h. Thesolution was diluted with Et₂O. The resulting solids were collected byfiltration, washed with Et₂O and dried to yield the title compound (33mg, 70%) as a yellow powder: mp 310-315° C. decomp.; ¹H NMR (500 MHz,DMSO-d₆) δ 11.54 (s, 1H), 8.90 (s, 2H), 8.70 (d, J=9.0 Hz, 1H), 8.46 (d,J=9.0 Hz, 1H), 7.89 (d, J=7.5 Hz, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.43 (d,J=1.5 Hz, 1H), 7.36 (d, J=2.0 Hz, 1H), 7.16 (dd, J=7.0, 2.0 Hz, 1H),7.08 (dd, J=8.5, 2.0 Hz, 1H), 4.44 (s, 2H), 3.48-3.46 (m, 2H), 3.05 (t,J=5.5 Hz, 2H), 2.03-2.01 (m, 2H); ESI MS m/z 426 [M+H]⁺; HPLC (Method A)97.3% (AUC), t_(R)=12.3 min.

Example 38 Preparation of4-(Benzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-onea)8-(4-Benzyloxy)-2-oxopyridin-1(2H)-yl)-6-methyl-2,3,4,5-tetrahydroazepino[4,3-b]indol-1(6H)-one

8-Bromo-6-methyl-2,3,4,5-tetrahydroazepino[4,3-b]indol-1(6H)-one (0.20g, 0.68 mmol), 4-benzyloxy pyridinone (0.18 g, 0.89 mmol), and Cs₂CO₃(0.24 g, 0.75 mmol) were suspended in DMSO (4.0 mL), and the air wasremoved under vacuum for 15 min. The system was flushed with Ar and theprocess repeated. 8-Hydroxyquinoline (30 mg, 0.21 mmol) and copperiodide (0.17 g, 0.89 mmol) were added to the suspension, and theevacuation/Ar flushing process was repeated twice more. The reactionmixture was heated at 130° C. for 18 h under N₂. The mixture was cooled,diluted with 5:1 MeOH/NH₄OH (10 mL), and the resulting solution wasstirred at ambient temperature for 30 min. The reaction was furtherdiluted with CH₂Cl₂ (75 mL). The solution was filtered through silicagel, and the filtrate was concentrated under reduced pressure. Theresidue was diluted with CH₂Cl₂ and washed with brine (3×25 mL). Theorganic solution was dried over Na₂SO₄, filtered and concentrated todryness under reduced pressure. Flash chromatography (12 g ISCO column,(1:1 hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 5 columnvolumes, increased to 50:50 over 20 column volumes and held for 4 columnvolumes; increased to 0:100 over 10 column volumes) followed by flashchromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2CH₂Cl₂/MeOH/NH₄OH), 100:0 for 5 column volumes, increased to 70:30 over20 column volumes and held for 4 column volumes; increased to 25:75 over10 column volumes) followed by trituration in hot EtOH provided thetitle compound (19 mg, 7%) as an off-white powder: mp 178-181° C.; ¹HNMR (500 MHz, DMSO-d₆) δ 8.29 (d, J=8.5 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H),7.53 (t, J=5.5 Hz, 1H), 7.49-7.35 (m, 6H), 7.00 (dd, J=8.5, 2.0 Hz, 1H),6.10 (dd, J=7.5, 2.5 Hz, 1H), 5.97 (d, J=2.5 Hz, 1H), 5.15 (s, 2H), 3.68(s, 3H), 3.21-3.10 (m, 2H), 3.12 (t, J=6.5 Hz, 2H), 2.08-2.07 (m, 2H);ESI MS m/z 414 [M+H]⁺; HPLC (Method A) 97.2% (AUC), t_(R)=16.5 min.

Example 39 Preparation of5-((5-Fluoropyridin-2-yl)methoxy)-2-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridazin-3(2H)-onehydrochloride a) tert-Butyl8-(4-((5-fluoropyridin-2-yl)methoxy)-6-oxopyridazin-1(6H)-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1)-carboxylate

tert-Butyl8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(0.31 g, 0.82 mmol),5-((5-fluoropyridin-2-yl)methoxy)pyridazin-3(2H)-one (0.20 g, 0.91mmol), and Cs₂CO₃ (0.35 g, 1.1 mmol) were suspended in DMSO (5.0 mL),and the air was removed under vacuum for 15 min. The system was flushedwith Ar, and the process was repeated. 8-Hydroxyquinoline (36 mg, 0.25mmol) and copper iodide (0.39 g, 2.1 mmol) were added to the suspension,the evacuation/Ar flushing process was repeated twice more, and thereaction mixture was heated at 130° C. for 18 h under positive N₂. Themixture was cooled, diluted with 5.0:3.5:1.5 NH₄Cl (aq)/NH₄OH/H₂O (40mL), and the resulting suspension was stirred at ambient temperature for30 min. The resulting solids were collected by filtration, dissolved inCH₂Cl₂ and washed with 5.0:3.5:1.5 NH₄Cl (aq)/NH₄OH/H₂O (3×30 mL). Theorganic solution was dried over Na₂SO₄, filtered and concentrated todryness. Flash chromatography (40 g ISCO column, (1:1hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 5 column volumes,increased to 50:50 over 12 column volumes and held for 4 column volumes;increased to 0:100 over 10 column volumes) followed by preparative HPLC(Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H₂O with 0.05% TFAand CH₃CN with 0.05% TFA) provided the title compound (83 mg, 19%) as ayellow powder: ¹H NMR (500 MHz, DMSO-d₆) δ 8.63 (d, J=3.0 Hz, 1H), 7.97(d, J=3.0 Hz, 1H), 7.84-7.82 (m, 1H), 7.70 (dd, J=9.0, 4.5 Hz, 1H),7.49-7.47 (m, 2H), 7.05 (d, J=9.0 Hz, 1H), 6.52 (d, J=2.0 Hz, 1H), 5.29(s, 2H), 4.59-4.57 (m, 2H), 3.66-3.65 (m, 5H), 2.99-298 (m, 2H),1.94-1.90 (m, 2H), 1.36-1.27 (m, 9H).

b)5-((5-Fluoropyridin-2-yl)methoxy)-2-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridazin-3(2H)-onehydrochloride

tert-Butyl-8-(4-(5-fluoropyridin-2yl)methoxy)-6-oxopyridazin-1(6H)-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(83 mg, 0.16 mmol) was treated with 1.25 M HCl in MeOH (9.5 mL) and theresulting solution was stirred at ambient temperature for 18 h. Thesolution was diluted with Et₂O and the resulting solids were collectedby filtration to provide the title compound (62 mg, 85%) as a lightbrown powder: ¹H NMR (500 MHz, DMSO-d₆) δ 8.97 (s, 2H), 8.63 (d, J=2.5Hz, 1H), 7.99 (d, J=3.0 Hz, 1H), 7.87-7.83 (m, 1H), 7.72-7.69 (m, 1H),7.64 (d, J=8.5 Hz, 1H), 7.57 (d, J=2.0 Hz, 1H), 7.13 (dd, J=8.5, 1.5 Hz,1H), 6.52 (d, J=3.0 Hz, 1H), 5.29 (s, 2H), 4.44-4.43 (m, 2H), 3.72 (s,3H), 3.45-3.43 (m, 2H), 3.10 (t, J=5.5 Hz, 2H), 2.07-2.05 (m, 2H); ESIMS m/z 420 [M+H]⁺; HPLC (Method A) 97.7% (AUC), t_(R)=12.3 min.

Example 40 Preparation of4-((5-Fluoropyridin-2-yl)methoxy-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-onehydrochloride a)tert-Butyl-8-(4-((5-(fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate

tert-Butyl8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate(0.15 g, 0.39 mmol),4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-one (0.13 g,0.52 mmol), and Cs₂CO₃ (0.14 g, 0.44 mmol) were suspended in DMSO (2.4mL), and the air was removed under vacuum for 15 min. The system wasflushed with Ar and 8-hydroxyquinoline (17 mg, 0.12 mmol) and copperiodide (98 mg, 0.52 mmol) were added to the suspension. Theevacuation/Ar flushing process was repeated twice more, and the reactionmixture was heated at 130° C. for 18 h under N₂. The mixture was cooled,diluted with 5:1 MeOH/NH₄OH (10 mL), and the resulting solution wasstirred at ambient temperature for 30 min. The reaction was furtherdiluted with CH₂Cl₂ (75 mL). The solution was filtered through silicagel, and the filtrate was concentrated under reduced pressure. Theresidue was diluted with CH₂Cl₂ and washed with brine (4×20 mL). Thesolution was dried over Na₂SO₄, filtered and concentrated to dryness.Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2CH₂Cl₂/MeOH/NH₄OH), 100:0 for 5 column volumes, increased to 50:50 over20 column volumes and held for 5 column volumes; increased to 0:100 over10 column volumes and held for 8 column volumes) provided the titlecompound (0.17 g, 52%) as an off-white solid: ¹H NMR (500 MHz, DMSO-d₆)δ 8.61 (d, J=2.5 Hz, 1H), 7.84-7.80 (m, 1H), 7.66-7.63 (m, 1H), 7.56 (d,J=7.5 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.37 (d, J=2.0 Hz, 1H), 6.89 (dd,J=8.5, 2.0 Hz, 1H), 6.11 (dd, J=7.5, 3.0 Hz, 1H), 5.95 (d, J=2.5 Hz,1H), 5.21 (s, 2H), 3.68-3.64 (m, 5H), 3.58-3.57 (m, 2H), 3.02-3.01 (m,2H), 2.94-2.93 (m, 2H), 1.43-1.42 (m, 9H); ESI MS m/z 519 [M+H]⁺.

b)4-((5-Fluoropyridin-2-yl)methoxy-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-onehydrochloride

tert-Butyl-8-(4-((5-(fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate(0.10 g, 0.12 mmol) in 1.25 M HCl in MeOH (26 mL) was stirred at ambienttemperature for 18 h. The mixture was concentrated to dryness underreduced pressure and diluted with MeOH (2.0 mL) and Et₂O (20 mL). Theresulting solids were collected by filtration and dried to provide thetitle compound (78 mg, 87%) as a yellow powder: mp 194-202° C. decomp;¹H NMR (500 MHz, DMSO-d₆) δ 9.25 (s, 2H), 8.62 (d, J=3.0 Hz, 1H),7.84-7.80 (m, 1H), 7.66-7.64 (m, 1H), 7.56 (dd, J=7.5 Hz, 1H), 7.51 (d,J=8.5 Hz, 1H), 7.42 (s, 1H), 6.94 (dd, J=8.5, 1.5 Hz, 1H), 6.12 (dd,J=7.5, 2.5 Hz, 1H), 5.96 (d, J=2.5 Hz, 1H), 5.12 (s, 2H), 3.68 (s, 3H),3.37-3.32 (m, 4H), 3.26-3.25 (m, 2H), 3.13-3.12 (m, 2H); ESI MS m/z 419[M+H]⁺; HPLC (Method A) 98.0% (AUC), t_(R)=12.5 min.

Example 41 Preparation of1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4(4-trifluoromethyl)phenyl)pyridin-2(1H)-onehydrochloride a) tert-Butyl6-methyl-8-(2-oxo-4(4-trifuoromethyl)phenyl)pyridin-1(2H)-yl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate

tert-Butyl8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate(0.15 g, 0.39 mmol), 4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one(0.12 g, 0.52 mmol), and Cs₂CO₃ (0.14 g, 0.44 mmol) were suspended inDMSO (2.4 mL), and the air was removed under vacuum for 15 min. Thesystem was flushed with Ar, and 8-hydroxyquinoline (17 mg, 0.12 mmol)and copper iodide (98 mg, 0.52 mmol) were added to the suspension. Theevacuation/Ar flushing process was repeated twice more, and the reactionmixture was heated at 130° C. for 18 h under N₂. The mixture was cooled,diluted with 5:1 MeOH/NH₄OH (20 mL), and the resulting solution wasstirred at ambient temperature for 30 min. The reaction was furtherdiluted with CH₂Cl₂ (75 mL). The solution was filtered through silicagel, and the filtrate was concentrated under reduced pressure. Theresidue was diluted with CH₂Cl₂ and washed with brine (3×20 mL). Theorganic solution was dried over Na₂SO₄, filtered and concentrated todryness. Flash chromatography (12 g ISCO column, (1:1hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 5 column volumes,increased to 50:50 over 20 column volumes and held for 4 column volumes;increased to 0:100 over 10 column volumes and held for 5 column volumes)followed by preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10micron, H₂O with 0.05% TFA and CH₃CN with 0.05% TFA) gave the titlecompound (81 mg, 38%) as a yellow film: ¹H NMR (300 MHz, DMSO-d₆) δ 7.99(d, J=8.4 Hz, 2H), 7.85 (d, J=8.4 Hz, 2H), 7.77 (d, J=6.9 Hz, 1H), 7.51(d, J=8.1 Hz, 1H), 7.47 (d, J=1.5 Hz, 1H), 6.98 (dd, J=8.1, 1.5 Hz, 1H),6.84 (d, J=1.8 Hz, 1H), 6.69 (dd, J=7.2, 2.1 Hz, 1H), 3.65-3.57 (m, 7H),3.01-2.94 (m, 4H), 1.15 (s, 9H); ESI MS m/z 538 [M+H]⁺.

b)1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4(4-trifluoromethyl)phenyl)pyridin-2(1H)-onehydrochloride

tert-Butyl6-methyl-8-(2-oxo-4(4-trifuoromethyl)phenyl)pyridin-1(2H)-yl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate(73 mg, 0.14 mmol) in 1.25 M HCl in MeOH (18 mL) was stirred at ambienttemperature for 18 h. The mixture was concentrated to dryness anddiluted with MeOH (2.0 mL) and Et₂O (20 mL). The resulting solids werecollected by filtration and dried to yield the title compound (44 mg,74%) as a yellow powder: mp 306-310° C. decomp.; ¹H NMR (500 MHz,DMSO-d₆) δ 9.29 (s, 2H), 8.00 (d, J=8.5 Hz, 2H), 7.88 (d, J=8.0 Hz, 2H),7.79 (d, J=7.0 Hz, 1H), 7.57 (d, J=8.5 Hz, 1H), 7.55 (d, J=1.0 Hz, 1H),7.05 (dd, J=8.5, 1.5 Hz, 1H), 6.86 (d, J=1.5 Hz, 1H), 6.71 (dd, J=7.0,2.0 Hz, 1H), 3.71 (s, 3H), 3.39-3.33 (m, 4H), 3.28-3.27 (m, 2H),3.16-3.13 (m, 2H); ESI MS m/z 438 [M+H]⁺; HPLC (Method A) 99.4% (AUC),t_(R)=15.3 min.

Example 42 Preparation of4-((5-Fluoropyridin-2-yl)methoxy)-1-(3-isopropyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-pyridin-2(1H)-onehydrochloride a)tert-Butyl-8-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-6-tosyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate

tert-Butyl-8-(4-((5-fluoropyridin-2-yl)methoxy-2-oxopyridin-1(2H)-yl)-6-tosyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate(0.31 g, 0.82 mmol), 4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one(0.15 g, 0.68 mmol), and Cs₂CO₃ (0.24 g, 0.75 mmol) were suspended inDMSO (5.0 mL), and the air was removed under vacuum for 15 min. Thesystem was flushed with Ar and 8-hydroxyquinoline (20 mg, 0.14 mmol) andcopper iodide (0.16 g, 0.82 mmol) were added to the suspension. Theevacuation/Ar flushing process was repeated twice more, and the reactionmixture was heated at 130° C. for 18 h under N₂. The mixture was cooled,diluted with 5.0:3.5:1.5 NH₄Cl(aq.)/NH₄OH/H₂O (40 mL), and the resultingsuspension was stirred at ambient temperature for 30 min. The resultingsolids were collected by filtration, dissolved in CH₂Cl₂(50 mL) andwashed with 5.0:3.5:1.5 NH₄Cl(aq.)/NH₄OH/H₂O (40 mL) (2×30 mL). Theresulting organic solution was dried over Na₂SO₄, filtered andconcentrated to dryness under reduced pressure. Flash chromatography (40g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0for 2 column volumes, increased to 50:50 over 12 column volumes and heldfor 5 column volumes; increased to 0:100 over 10 column volumes and heldfor 5 column volumes) provided the title compound (0.15 g, 34%) as ayellow film: ¹H NMR (500 MHz, CDCl₃) δ 8.48 (d, J=2.5 Hz, 1H), 8.24 (s,1H), 7.66-7.63 (m, 2H), 7.52-7.45 (m, 2H), 7.42 (d, J=8.0 Hz, 1H), 7.33(d, J=7.5 Hz, 1H), 7.26-7.22 (m, 3H), 6.12 (dd, J=7.5, 2.5 Hz, 1H), 6.06(d, J=3.0 Hz, 1H), 5.18 (s, 2H), 3.67-3.62 (m, 4H), 3.36-3.34 (m, 2H),2.94-2.90 (m, 2H), 2.34 (s, 3H), 1.46-1.44 (m, 9H).

b) tert-Butyl8-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H))-carboxylate

NaOH (1.2 g, 30 mmol) was added to a solution oftert-butyl-8-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-6-tosyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate(0.15 g, 0.23 mmol) in 1:1 CH₂Cl₂/MeOH (14 mL), and the resultingsolution was stirred at ambient temperature for 18 h. The mixture wasdiluted with H₂O and extracted with CH₂Cl₂ (3×25 mL). The combinedorganic extracts were dried over Na₂SO₄ and concentrated under reducedpressure to dryness. Flash chromatography (12 g ISCO column,CH₂Cl₂/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 5 column volumes,increased to 25:75 over 20 column volumes and held for 12 columnvolumes) provided the title compound (84 mg, 72%) as an off-white film:¹H NMR (500 MHz, DMSO-d₆) δ 10.97 (s, 1H), 8.62 (d, J=3.0 Hz, 1H),7.83-7.80 (m, 1H), 7.66-7.64 (m, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.44 (d,J=8.0 Hz, 1H), 7.18 (s, 1H), 6.85 (dd, J=8.0, 1.5 Hz, 1H), 6.09 (dd,J=8.0, 3.0 Hz, 1H), 5.95 (d, J=3.0 Hz, 1H), 5.20 (s, 2H), 3.59-3.57 (s,4H), 2.96-2.94 (m, 2H), 2.88-2.86 (m, 2H), 1.43 (s, 9H).

c)4-((5-Fluoropyridin-2-yl)methoxy)-1-(1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-pyridin-2(1H)-one

tert-Butyl8-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H))-carboxylate(80 mg, 0.16 mmol) was treated with 1.25 M HCl in MeOH (7.5 mL), and theresulting solution was stirred at ambient temperature for 18 h. Thesolution was concentrated to dryness to provide the title compound (100mg, quantitative) as a brown solid: ¹H NMR (300 MHz, DMSO-d₆) δ 11.21(s, 1H), 9.32 (s, 2H), 8.62 (s, 1H), 7.85-7.80 (m, 1H), 7.67-7.63 (m,1H), 7.56 (d, J=7.5 Hz, 1H), 7.50-7.47 (m, 1H), 7.24 (s, 1H), 6.89 (d,J=8.4 Hz, 1H), 6.12-6.07 (m, 1H), 5.96-5.95 (m, 1H), 5.21 (s, 2H),3.34-3.32 (m, 4H), 3.19-3.16 (m, 2H), 3.11-3.09 (m, 2H).

d)4-((5-Fluoropyridin-2-yl)methoxy)-1-(3-isopropyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-pyridin-2(1H)-one

AcOH (0.42 mL) and picoline borane complex (51 mg, 0.47 mmol) were addedto4-((5-fluoropyridin-2-yl)methoxy)-1-(1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-pyridin-2(1H)-one(69 mg, 0.16 mmol) suspended in 1:1 CH₂Cl₂/acetone (4.8 mL), and theresulting suspension was heated at reflux for 68 h. Additional acetone(1.0 mL) and picoline borane complex (20 mg, 19 mmol) were added, andthe resulting suspension heated at reflux for 68 h. The reaction wascooled and concentrated to dryness under reduced pressure. 1 N HCl (10ml) was added, and the suspension stirred at ambient temperature for 2h. The mixture was made basic with 1 N NaOH and extracted with CH₂Cl₂(3×20 mL). The combined organic extracts were dried over Na₂SO₄,filtered and concentrated to dryness under reduced pressure. PreparativeTLC (Analtech, 20×20 cm, 1000 microns, 80:18:2 CH₂Cl₂/MeOH/NH₄OH)provided the title compound (31 mg, 43%) as an off-white solid: ¹H NMR(500 MHz, DMSO-d₆) δ 10.86 (s, 1H), 8.61 (d, J=2.5 Hz, 1H), 7.82-7.81(m, 1H), 7.66-7.63 (m, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.40 (d, J=8.5 Hz,1H), 7.14 (s, 1H), 6.82 (d, J=7.0 Hz, 1H), 6.09 (dd, J=7.5, 3.0 Hz, 1H),5.95 (d, J=3.0 Hz, 1H), 5.20 (s, 2H), 3.02-2.98 (m, 1H), 2.86-2.85 (m,2H), 2.76 (m, 6H), 1.02 (d, J=6.5 Hz, 6H); ESI MS m/z 447 [M+H]⁺.

e)4-((5-Fluoropyridin-2-yl)methoxy)-1-(3-isopropyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-pyridin-2(1H)-onehydrochloride

1.25 M HCl in MeOH (48 μL, 0.060 mmol) was added to a solution of4-((5-fluoropyridin-2-yl)methoxy)-1-(3-isopropyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-pyridin-2(1H)-one(27 mg, 0.060 mmol) in MeOH (2.0 mL), and the resulting solution wasstirred at ambient temperature for 18 h. The mixture was concentrated todryness to provide the title compound (26 mg, 90%) as an off-whitepowder: ESI MS m/z 447 [M+H]⁺; HPLC (Method A) 97.6% (AUC), t_(R)=12.7min.

Example 43 Preparation of4-(Benzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-onehydrochloride

tert-Butyl8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate(80 mg, 0.33 mmol) and Cs₂CO₃ (390 mg, 0.38 mmol) were suspended in DMSO(8.0 mL) and degassed under vacuum for 15 min. The system was thenflushed with Ar, and 8-hydroxyquinoline (30 mg, 0.18 mmol) and copperiodide (80 mg, 0.40 mmol) were added. The degassing/Ar flushing processwas repeated twice, and the reaction mixture was heated to 133° C. for18 h under argon. The mixture was cooled, diluted with 17:3 MeOH/NH₄OH(25 mL) and stirred at ambient temperature for 30 min. The reaction wasfurther diluted with CH₂Cl₂ (75 mL). The solution was filtered throughsilica gel and concentrated under reduced pressure. The residue wasdiluted with CH₂Cl₂. The resulting solution was washed with H₂O (2×25mL) and brine (3×50 mL). The combined organics were dried over Na₂SO₄,filtered and concentrated under reduced pressure to dryness. Flashchromatography purification (silica gel, (A=1:1hexanes/EtOAc)/B=10:1:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) provided awhite solid. TFA (2 mL) was added to a solution of the white solid in1:1 MeOH/CH₂Cl₂, and the resulting mixture was stirred at ambienttemperature for 30 min. The solvent was removed under reduced pressure,and the residue was neutralized by ion-exchange chromatography (SCX-2column, 2 g). Preparative TLC (silica gel, 10:1:0.1 CH₂Cl₂/MeOH/NH₄OH)provided a white foam. The white foam was dissolved in methanol (5 mL)and treated with 1.25 M HCl in MeOH (0.3 mL). The resulting solution wasstirred for 5 min at ambient temperature. The mixture was concentrated,and the resulting residue was lyophilized from water (5 mL) to affordthe title compound (58 mg, 18%) as a white powder: ¹H NMR (500 MHz,DMSO-d₆) δ 9.34 (br s, 2H), 7.55-7.37 (m, 8H), 6.94 (dd, J=8.0, 1.0 Hz,1H), 6.09 (dd, J=9.0 Hz, 1.0, 1H), 5.96 (s, 1H), 5.15 (s, 2H), 3.68 (s,3H), 3.36-3.26 (m, 6H), 3.14-3.12 (m, 2H); ESI MS m/z 400 [M+H]⁺; HPLC(Method A) 97.9% (AUC), t_(R)=14.4 min.

Example 44 Preparation of4-(benzyloxy)-1-(3,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-onehydrochloride

To a solution of4-(benzyloxy)-1-(3,6-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-one(270 mg, 0.65 mmol) in 99:1 CH₂Cl₂/AcOH (10 mL) were added formaldehyde(38% solution in water, 100 μL, 1.3 mmol), and NaBH(OAc)₃ (550 mg, 2.6mmol), and the reaction mixture was stirred at ambient temperature for18 h. The mixture was concentrated, and the residue was dissolved inCH₂Cl₂. The organic layer was washed with brine, water, dried withNa₂SO₄, filtered and concentrated under reduced pressure. Flashchromatography (silica gel, (A=dichloromethane, B=10:1:0.1CH₂Cl₂/MeOH/NH₄OH, 100:0 to 0:100), followed by purification bypreparative TLC (silica gel, 10:1:0.1dichloromethane/methanol/concentrated ammonium hydroxide) provided awhite solid (58 mg). The white solid was dissolved in methanol (5 mL)and treated with 1.25 M HCl in MeOH (1 mL). The resulting solution wasstirred for 5 min at ambient temperature. The mixture was concentrated,and the resulting residue was lyophilized from water (5 mL) to affordthe title compound (48 mg, 16%) as a white powder: ¹H NMR (500 MHz,CD₃OD) δ 7.58 (dd, J=8.5 Hz, 3.0 Hz, 2H), 7.46 (dd, J=8.0 Hz, 2.0 Hz,2H), 7.43-7.39 (m, 3H), 7.37-7.35 (m, 1H), 7.01 (dd, J=8.5, 2.0 Hz, 1H),6.31 (dd, J=7.5, 2.5 Hz, 1H), 6.13 (d, J=1.5 Hz, 1H), 5.18 (s, 2H),3.81-3.75 (m, 2H), 3.73 (s, 3H), 3.60-3.42 (m 2H), 3.41-3.32 (m, 2H);3.20-3.10 (m, 2H), 3.08 (s, 3H); ESI MS m/z 414 [M+H]⁺; HPLC (Method A)99.8% (AUC), t_(R)=14.2 min.

Example 45 Preparation of1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-((6-methylpyridin-3-yl)methoxy)pyridin-2(1H)-onedihydrochloride

A suspension of 4-((6-methylpyridin-3-yl)methoxy)pyridin-2(1H)-one (82mg, 0.38 mmol), tert-butyl8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate(158 mg, 0.42 mmol), CuI (87 mg, 0.46 mmol), 8-hydroxyquinoline (11 mg,0.076 mmol) and Cs₂CO₃ (136 mg, 0.42 mmol) in DMSO (10 mL) was degassedunder reduced pressure for 45 min. The suspension was put under N₂ andstirred at 135° C. for 8 h. The suspension was cooled, 9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension wasstirred at 25° C. for 30 min. The suspension was passed through a plugof silica gel, and the filtrate was washed with brine. Activated carbonwas added to the solution, and the resulting suspension was filtered.The filtrate was dried over Na₂SO₄ and concentrated under reducedpressure. Flash chromatography (silica gel, (1:1EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) affordedan off-white solid. 1.25 N HCl in MeOH (5 mL) was added to the off-whitesolid under N₂, and the resulting suspension was stirred at 25° C. for18 h. The suspension was concentrated, and the residue was freeze driedto afford the title compound (105 mg, 57%) as an off-white solid: ¹H NMR(500 MHz, DMSO-d₆) δ 9.23 (br s, 2H), 8.81 (s, 1H), 8.40-8.25 (m, 1H),7.82-7.75 (m, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.42(d, J=2.0, 1H), 6.94 (dd, J=8.5, 2.0 Hz, 1H), 6.12 (dd, J=8.0, 3.0 Hz,1H), 6.02 (d, J=2.5 Hz, 1H), 5.28 (s, 2H), 3.69 (s, 3H), 3.41-3.29 (m,4H), 3.28-3.22 (m, 2H), 3.15-3.10 (m, 2H), 2.68 (s, 3H); ESI MS m/z 415[M+H]⁺.

Example 46 Preparation of1-(3-Acetyl-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one

A suspension of 4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one(2.21 g, 5.83 mmol), tert-butyl8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate(1.54 g, 6.41 mmol), CuI (1.33 g, 6.99 mmol), 8-hydroxyquinoline (169mg, 1.17 mmol) and Cs₂CO₃ (2.09 g, 6.41 mmol) in DMSO (30 mL) wasdegassed under reduced pressure for 45 min. The suspension was put underN₂ and stirred at 135° C. for 15 h. The suspension was cooled, 9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension wasstirred at 25° C. for 20 min. The suspension was passed through a plugof silica gel, and the filtrate was washed with brine. Activated carbonwas added to the resulting solution, and the resulting suspension wasfiltered. The filtrate was dried over Na₂SO₄ and concentrated underreduced pressure. Flash chromatography on silica gel ((1:1EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded ayellow solid. 2 N HCl in Et₂O (100 mL) was added to a solution of theyellow solid in 1:1 CH₂Cl₂/MeOH (2 mL) under N₂, and the resultingsuspension was stirred at 25° C. for 19 h. The suspension was filteredand the solid was washed with Et₂O, CH₂Cl₂, and Et₂O in succession. Thematerial was dried in a vacuum oven at 60° C. for 3 d to afford 1.70 gof a yellow solid. Preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0mm, 10 micron, H₂O with 0.05% TFA and CH₃CN with 0.05% TFA) of 184 mg ofthe yellow solid afforded 59 mg of a yellow solid. AcCl (0.02 mL, 0.20mmol) was added to a solution of the yellow solid, DMAP (3 mg, 0.03mmol) and Et₃N (0.04 mL, 0.27 mmol) in CH₂Cl₂ (20 mL) under N₂, and theresulting solution was stirred at 25° C. for 2 h. The reaction solutionwas concentrated under reduced pressure. Flash chromatography on silicagel ((1:1 EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100)afforded 61 mg (20%) of the title compound as a yellow powder as amixture of rotomers: ¹H NMR (500 MHz, DMSO-d₆) δ 9.20 (s, 1H), 8.49 (dd,J=8.0, 2.0 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.84 (d, J=7.0 Hz, 1H), 7.55(d, J=8.5 Hz, 1H), 7.53-7.50 (m, 1H), 7.04-6.99 (m, 2H), 6.79 (dd,J=7.0, 2.0 Hz, 1H), 3.85-3.65 (m, 7H), 3.14-2.93 (m, 4H), 2.14 (s,1.2H), 2.09 (s, 1.8H); ESI MS m/z 481 [M+H]⁺.

Example 47 Preparation of2-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-5-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridazin-3(2H)-onehydrochloride

a) 5-Hydroxy-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (CASRegistry Number 1008517-74-5) (WO 2008/022979 to Stenkamp et al., whichis hereby incorporated by reference in its entirety)

This compound was prepared in accordance with the procedure of Stenkampet al., WO 2008/022979, which is hereby incorporated by reference in itsentirety.

b)2-(Tetrahydro-2H-pyran-2-yl)-5-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridazin-3(2H)-one

5-Hydroxy-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (2.3 g, 12mmol), 5-(bromomethyl)-2-(trifluoromethyl)pyridine (7.2 g, 30 mmol) andK₂CO₃ (8.4 g, 60 mmol) were stirred in DMF (40 ml) and CH₂Cl₂ (40 ml)for 48 h. The mixture was diluted with CH₂Cl₂, washed with 5% LiClsolution (4×) and concentrated. The residue was purified by columnchromatography (40 g ISCO column column eluting with methylene chlorideand a 10:1 methanol/ammonium hydroxide mixture; gradient 100% methylenechloride to 95% methylene chloride) to yield the title compound (5.25g, >100%) as a waxy white solid containing some DMF: ¹H NMR (300 MHz,CDCl₃) δ 8.78 (d, J=1.8 Hz, 1H), 7.97-7.88 (m, 1H), 7.76 (d, J=7.9 Hz,1H), 7.72 (m, 1H), 6.20 (d, J=2.9 Hz, 1H), 6.03-5.98 (d, J=10.9, 2.0 Hz,1H), 5.11 (s, 2H), 4.16-4.08 (m, 1H), 3.79-3.69 (m, 1H), 2.24-1.96 (m,2H), 1.83-1.48 (m, 4H).

c) 5-((6-(Trifluoromethyl)pyridin-3-yl)methoxy)pyridazin-3(2H)-one

2-(Tetrahydro-2H-pyran-2-yl)-5-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridazin-3(2H)-one(5.25 g, 12 mmol estimated) was stirred in MeOH (10 mL), and 2 N HCl inEt₂O (50 mL) was added. After 16H, the mixture was diluted with Et₂O(100 mL), and the solid was filtered off. The solid was stirred inNaHCO₃ solution (15 mL) for 15 minutes and then refiltered to providethe title compound (2.2 g, 67%) as a white solid: ¹H NMR (300 MHz,DMSO-d₆) δ 12.74 (s, 1H), 8.78 (s, 1H), 8.20-8.16 (dd, J=8.1, 1.5 Hz,1H), 8.00 (d, J=8.1 Hz, 1H), 7.76 (d, J=2.6 Hz, 1H), 6.31 (s, 1H), 5.25(s, 2H).

d)2-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-5-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridazin-3(2H)-onehydrochloride

A suspension of5-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridazin-3(2H)-one (140 mg,0.519 mmol), tert-butyl8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate(164 mg, 0.433 mmol), CuI (99 mg, 0.52 mmol), 8-hydroxyquinoline (13 mg,0.087 mmol) and Cs₂CO₃ (155 mg, 0.476 mmol) in DMSO (10 mL) was degassedunder reduced pressure for 45 min. The suspension was put under N₂ andstirred at 135° C. for 40 h. The suspension was cooled, 9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension wasstirred at 25° C. for 20 min. The suspension was passed through a plugof silica gel, and the filtrate was washed with brine. Activated carbonwas added to the resulting solution, and the resulting suspension wasfiltered. The filtrate was dried over Na₂SO₄ and concentrated underreduced pressure. Flash chromatography on silica gel ((1:1EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) affordedan off-white solid. 2 N HCl in Et₂O (100 mL) was added to a solution ofthe off-white solid in 1:1 CH₂Cl₂/MeOH (2 mL) under N₂, and theresulting suspension was stirred at 25° C. for 19 h. The suspension wasfiltered, and the solid was washed with Et₂O to afford 42 mg (19%) ofthe title compound as an off-white solid: mp 270-274° C.; ¹H NMR (500MHz, DMSO-d₆) δ 9.02-8.91 (m, 3H), 8.23 (d, J=8.5 Hz, 1H), 8.02 (d,J=8.0 Hz, 1H), 8.00 (d, J=2.5, 1H), 7.55-7.51 (m, 2H), 7.09 (dd, J=8.5,2.0 Hz, 1H), 6.56 (d, J=3.0 Hz, 1H), 5.42 (s, 2H), 3.69 (s, 3H),3.44-3.28 (m, 4H), 3.27-3.21 (m, 2H), 3.13-3.09 (m, 2H); ESI MS m/z 470[M+H]⁺.

Example 48 Preparation of1-(3-Acetyl-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one

AcCl (0.01 mL, 0.2 mmol) was added to a solution of4-((5-fluoropyridin-2-yl)methoxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-onehydrochloride (49 mg, 0.11 mmol), DMAP (3 mg, 0.03 mmol), and Et₃N (0.03mL, 0.3 mmol) in CH₂Cl₂ (10 mL) under N₂, and the resulting solution wasstirred at 25° C. for 4 h. H₂O was added and the resulting phases wereseparated. The organic phase was dried over Na₂SO₄ and concentratedunder reduced pressure. Flash chromatography on silica gel ((1:1EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded39 mg (78%) of the title compound as a white solid as a mixture ofrotomers: mp 88-94° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 8.62 (d, J=3.0 Hz,1H), 7.84 (ddd, J=9.0, 9.0, 3.0 Hz, 1H), 7.66 (dd, J=8.5, 4.5 Hz, 1H),7.57 (d, J=8.0 Hz, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.38 (dd, J=3.0, 1.5 Hz,1H), 6.92-6.88 (m, 1H), 6.12 (dd, J=7.5, 3.0 Hz, 1H), 5.96 (d, J=2.5 Hz,1H), 5.22 (s, 2H), 3.82-3.76 (m, 2H), 3.75-3.63 (m, 5H), 3.10 (t J=5.5,1H), 3.05-2.98 (m, 2H), 2.93 (t, J=5.5, 1H), 2.13 (s, 1.5H), 2.08 (s,1.5H); ESI MS m/z 461 [M+H]⁺.

Example 49 Preparation of1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-(4-(trifluoromethyl)phenyl)pyrimidin-2(1H)-onehydrochloride a) 4-(4-(Trifluoromethyl)phenyl)pyrimidin-2(1H)-one (CASRegistry Number 1159816-20-2)

A suspension of 4-chloro-2-methoxypyrimidine (500 mg, 3.47 mmol),4-(trifluoromethyl)phenylboronic acid (788 mg, 4.17 mmol), PdCl₂(dppf)(283 mg, 0.347 mmol) and K₂CO₃ (958 mg, 6.94 mmol) in DMSO (10 mL) wasdegassed under reduced pressure for 45 min. The suspension was put underN₂ and stirred at 95° C. for 20 h. The suspension was cooled, H₂O wasadded and the suspension was filtered to afford a light colored solid.Flash chromatography on silica gel (hexanes/(1:1 EtOAc/hexanes), 100:0to 0:100) afforded a white solid. The white solid was diluted withconcentrated HCl solution (10 mL) and stirred at reflux for 4 h. Thereaction was cooled, and the solution was neutralized with saturatedNaHCO₃ solution. The resulting suspension was filtered to afford 185 mg(22%) of the title compound as a white solid: ESI MS m/z 241 [M+H]⁺.

b)1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-(4-(trifluoromethyl)phenyl)pyrimidin-2(1H)-onehydrochloride

A suspension of 4-(4-(trifluoromethyl)phenyl)pyrimidin-2(1H)-one (72 mg,0.30 mmol), tert-butyl8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate(136 mg, 0.358 mmol), CuI (68 mg, 0.36 mmol), 8-hydroxyquinoline (9 mg,0.06 mmol) and Cs₂CO₃ (107 mg, 0.329 mmol) in DMSO (10 mL) was degassedunder reduced pressure for 45 min. The suspension was put under N₂ andstirred at 135° C. for 17 h. The suspension was cooled, 9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension wasstirred at 25° C. for 30 min. The suspension was passed through a plugof silica gel, and the filtrate was washed with brine. Activated carbonwas added to the resulting solution, and the resulting suspension wasfiltered. The filtrate was dried over Na₂SO₄ and concentrated underreduced pressure. Flash chromatography on silica gel ((1:1EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded ayellow solid. 2 N HCl in Et₂O (100 mL) was added to a solution of theyellow solid in CH₂Cl₂ (5 mL) under N₂, and the resulting suspension wasstirred at 25° C. for 15 h. The suspension was filtered, and the solidwas washed with 9:1 CH₂Cl₂/MeOH and Et₂O in succession to afford 53 mg(37%) of the title compound as an orange solid: ¹H NMR (500 MHz,DMSO-d₆) δ 9.10 (br s, 2H), 8.40 (d, J=8.0 Hz, 2H), 8.38 (d, J=7.0 Hz,1H), 7.95 (d, J=8.5 Hz, 2H), 7.65 (d, J=1.5, 1H), 7.59 (d, J=8.5 Hz,1H), 7.27 (d, J=7.0 Hz, 1H), 7.14 (dd, J=8.0, 1.5 Hz, 1H), 3.72 (s, 3H),3.43-3.32 (m, 4H), 3.29-3.24 (m, 2H), 3.16-3.12 (m, 2H); ESI MS m/z 439[M+H]⁺.

Example 50 Preparation of4-((5-Chloropyridin-2-yl)methoxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-onehydrochloride

a) 4((5-Chloropyridin-2-yl)methoxy)pyridine 1-oxide (CAS Registry Number1039826-88-4) (WO 2008/086404 to Guzzo et al., which is herebyincorporated by reference in its entirety)

5-Chloro-2-pyridylbenzylalcohol (4.9 g, 34 mmol) and4-chloropyridine-N-oxide (2.94 g, 22.7 mmol) were reacted according toExample 34 (step a) to provide the title compound (2.2 g, 40%) as a tansolid: ¹H NMR (300 MHz, CDCl₃) δ 8.58 (d, J=2.2 Hz, 1H), 8.13 (d, J=7.7Hz, 2H), 7.74 (dd, J=8.4, 2.5 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 6.90 (d,J=7.7 Hz, 2H), 5.20 (s, 2H).

b) 4((5-Chloropyridin-2-yl)methoxy)pyridin-2 (1H)-one (CAS RegistryNumber 924311-89-7) (WO 2007/018248 to Ando et al., which is herebyincorporated by reference in its entirety)

4-((5-Chloropyridin-2-yl)methoxy)pyridine 1-oxide (2.2 g, 9.2 mmol) wasreacted according to Example 34 (step b) to provide the title compound(1.52 g, 69%) as a tan solid: ¹H NMR (500 MHz, CD₃OD) δ 8.56 (d, J=2.3Hz, 1H), 7.91-7.89 (dd, J=8.4, 2.5 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.34(d, J=8.3 Hz, 1H), 6.21-6.19 (dd, J=7.2, 2.5 Hz, 1H), 5.97 (d, J=2.4 Hz,1H), 5.18 (s, 2H).

c)4-((5-Chloropyridin-2-yl)methoxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-onehydrochloride

A suspension of 4-((5-chloropyridin-2-yl)methoxy)pyridin-2(1H)-one (116mg, 0.489 mmol), tert-butyl8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate(204 mg, 0.538 mmol), CuI (111 mg, 0.587 mmol), 8-hydroxyquinoline (14mg, 0.10 mmol) and Cs₂CO₃ (175 mg, 0.381 mmol) in DMSO (10 mL) wasdegassed under reduced pressure for 45 min. The suspension was put underN₂ and stirred at 135° C. for 19 h. The suspension was cooled, 9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension wasstirred at 25° C. for 30 min. The suspension was passed through a plugof silica gel, and the filtrate was washed with brine. Activated carbonwas added to the resulting solution, and the resulting suspension wasfiltered. The filtrate was dried over Na₂SO₄ and concentrated underreduced pressure. Flash chromatography on silica gel ((1:1EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH) afforded a tan solid. 2 NHCl in Et₂O (100 mL) was added to a solution of the tan solid in CH₂Cl₂(5 mL) under N₂, and the resulting suspension was stirred at 25° C. for15 h. The suspension was filtered, and the solid was washed with Et₂Oand freeze dried to afford 82 mg (36%) of the title compound as a lightyellow solid: ¹H NMR (500 MHz, DMSO-d₆) δ 9.14 (br s, 2H), 8.78 (d,J=2.5 Hz, 1H), 8.03 (dd, J=8.5, 2.5 Hz, 1H), 7.61 (d, J=8.5 Hz, 1H),7.57 (d, J=7.5 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.43 (d, J=1.5 Hz, 1H),6.94 (dd, J=8.0. 1.5 Hz, 1H), 6.14 (dd, J=7.5, 3.0 Hz, 1H), 5.95 (d,J=2.5 Hz, 1H), 5.23 (s, 2H), 3.69 (s, 3H), 3.40-3.30 (m, 4H), 3.26-3.22(m, 2H), 3.13-3.09 (m, 2H); ESI MS m/z 435 [M+H]⁺.

Example 51 Preparation of4-(2,4-Dichlorobenzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-one

a) 4-(2,4-Dichlorobenzyloxy)pyridin-2(1H)-one (CAS Registry Number1182243-20-4) (WO 2007/043,835 to Kim et al., which is herebyincorporated by reference in its entirety)

A suspension of (2,4-dichlorophenyl)methanol (4.10 g, 23.2 mmol),2-chloro-4-iodopyridine (5.05 g, 21.1 mmol), Cs₂CO₃ (8.94 g, 27.4 mmol),CuI (4.01 g, 21.1 mmol) and 1,10-phenanthroline (760 mg, 4.22 mmol) intoluene (20 mL) was degassed by bubbling N₂ through the suspension for15 min. The suspension was put under N₂, and heated at 105° C. for 18 h.The suspension was cooled, EtOAc (50 mL) was added, and the resultingsuspension was passed through a plug of SiO₂. The resulting solution wasconcentrated under reduced pressure. Flash chromatography on silica gel(hexanes/(1:1 EtOAc/hexanes), 100:0 to 0:100) afforded a white solid. Asuspension of the white solid and NH₄OAc (6.13 g, 79.5 mmol) in 1:1HCO₂H/H₂O (40 mL) was heated at reflux with stirring for 4 d. Thesolution was cooled and concentrated under reduced pressure. Theresulting residue was made basic with saturated NaHCO₃ solution and theresulting suspension was filtered. The solid was washed with H₂O anddried under reduced pressure. Flash chromatography on silica gel ((1:1EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded1.36 g (24%) of the title compound as a white solid: ¹H NMR (300 MHz,DMSO-d₆) δ 11.16 (br s, 1H), 7.71 (d, J=2.1 Hz, 1H), 7.61 (d, J=8.1,1H), 7.50 (dd, J=8.4, 2.1 Hz, 1H), 7.26 (d, J=7.2 Hz, 1H), 5.91 (dd,J=7.5, 2.7 Hz, 1H), 5.81 (d, J=2.4 Hz, 1H), 5.10 (s, 2H).

b) 4-(2,4-Dichlorobenzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-one

A suspension of 4-(2,4-dichlorobenzyloxy)pyridin-2(1H)-one (103 mg,0.381 mmol), tert-butyl8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate(131 mg, 0.347 mmol), CuI (79 mg, 0.42 mmol), 8-hydroxyquinoline (10 mg,0.069 mmol) and Cs₂CO₃ (124 mg, 0.381 mmol) in DMSO (10 mL) was degassedunder reduced pressure for 45 min. The suspension was put under N₂ andstirred at 135° C. for 48 h. The suspension was cooled, 9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension wasstirred at 25° C. for 30 min. The suspension was passed through a plugof silica gel, and the filtrate was washed with brine. Activated carbonwas added to the resulting solution, and the resulting suspension wasfiltered. The filtrate was dried over Na₂SO₄, and concentrated underreduced pressure. Flash chromatography on silica gel (Et₂O/(8:1.9:0.1Et₂O/MeOH/NH₄OH), 100:0 to 0:100) afforded a tan solid. 2 N HCl in Et₂O(100 mL) was added to a solution of the tan solid in CH₂Cl₂ (5 mL) underN₂, and the resulting suspension was stirred at 25° C. for 17 h. Thesuspension was filtered, and the solid was washed with Et₂O and freezedried to afford 66 mg (38%) of the title compound as a white powder: ¹HNMR (500 MHz, DMSO-d₆) δ 9.02 (br s, 2H), 7.74 (d, J=2.0 Hz, 1H), 7.66(d, J=8.5 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.54-7.50 (m, 2H), 7.45 (d,J=1.5 Hz, 1H), 6.96 (dd, J=8.5, 2.0 Hz, 1H), 6.10 (dd, J=7.5, 3.0 Hz,1H), 6.00 (d, J=3.0 Hz, 1H), 5.19 (s, 2H), 3.69 (s, 3H), 3.42-3.31 (m,4H), 3.26-3.22 (m, 2H), 3.13-3.09 (m, 2H); ESI MS m/z 468 [M+H]⁺.

Example 52 Preparation of4-(2,4-Difluorobenzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-onehydrochloride

a) 4-(2,4-Difluorobenzyloxy)pyridin-2(1H)-one (CAS Registry Number586373-58-2) (WO 2003/068230 to Devadas et al., which is herebyincorporated by reference in its entirety)

A suspension of (2,4-difluorophenyl)methanol (4.86 g, 33.7 mmol),2-chloro-4-iodopyridine (7.35 g, 30.7 mmol), Cs₂CO₃ (14.3 g, 43.8 mmol),CuI (5.83 g, 30.7 mmol) and 1,10-phenanthroline (1.11 g, 6.14 mmol) intoluene (20 mL) was degassed by bubbling N₂ through the suspension for15 min. The suspension was put under N₂, and heated at 105° C. for 18 h.The suspension was cooled, EtOAc (50 mL) was added, and the resultingsuspension was passed through a plug of SiO₂. The resulting solution wasconcentrated under reduced pressure. Flash chromatography on silica gel(hexanes/(1:1 EtOAc/hexanes), 100:0 to 0:100) afforded a white solid. Asuspension of the white solid and NH₄OAc (8.21 g, 107 mmol) in 1:1HCO₂H/H₂O (40 mL) was heated at reflux with stirring for 4 d. Thesolution was cooled and concentrated under reduced pressure. Theresulting residue was made basic with saturated NaHCO₃ solution, and theresulting suspension was filtered. The solid was washed with H₂O anddried under reduced pressure to afford 3.16 g (44%) of the titlecompound as a white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 11.14 (br s, 1H),7.62 (br dd, J=15.3, 8.7 Hz, 1H), 7.33 (ddd, J=10.5, 10.5, 2.4 Hz, 1H),7.25 (d, J=7.2 Hz, 1H), 7.12 (ddd, J=8.4, 8.4, 1.8 Hz, 1H), 5.91-5.82(m, 2H), 5.06 (s, 2H).

b)4-(2,4-Difluorobenzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-onehydrochloride

A suspension of 4-(2,4-difluorobenzyloxy)pyridin-2(1H)-one (114 mg,0.479 mmol), tert-butyl8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate(165 mg, 0.435 mmol), CuI (99 mg, 0.52 mmol), 8-hydroxyquinoline (13 mg,0.087 mmol) and Cs₂CO₃ (156 mg, 0.479 mmol) in DMSO (10 mL) was degassedunder reduced pressure for 45 min. The suspension was put under N₂ andstirred at 135° C. for 2 d. The suspension was cooled, 9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension wasstirred at 25° C. for 30 min. The suspension was passed through a plugof silica gel, and the filtrate was washed with brine. Activated carbonwas added to the resulting solution, and the resulting suspension wasfiltered. The filtrate was dried over Na₂SO₄, and concentrated underreduced pressure. Flash chromatography on silica gel (Et₂O/(8:1.9:0.1Et₂O/MeOH/NH₄OH) afforded a yellow residue. 2 N HCl in Et₂O (100 mL) wasadded to a solution of the yellow residue in CH₂Cl₂ (5 mL) under N₂, andthe resulting suspension was stirred at 25° C. for 2 d. The suspensionwas filtered, and the solid was washed with Et₂O and put in a vacuumoven at 45° C. for 2 h to afford 98 mg (48%) of the title compound as awhite powder: ¹H NMR (500 MHz, DMSO-d₆) δ 9.02 (br s, 2H), 7.67 (dd,J=15.0, 9.0 Hz, 1H), 7.54 (d, J=7.5 Hz, 1H), 7.52 (d, J=8.5 Hz, 1H),7.44 (d, J=1.5 Hz, 1H), 7.35 (ddd, J=10.5, 10.5, 2.0 Hz, 1H), 7.18 (ddd,J=8.5, 8.5, 2.5 Hz, 1H), 6.95 (dd, J=8.5, 2.0 Hz, 1H), 6.07 (dd, J=7.5,3.0 Hz, 1H), 6.04 (d, J=3.0 Hz, 1H), 5.15 (s, 2H), 3.69 (s, 3H),3.41-3.31 (m, 4H), 3.26-3.22 (m, 2H), 3.14-3.10 (m, 2H); ESI MS m/z 436[M+H]⁺.

Example 53 Preparation of4-(4-Chlorophenethyl)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)piperazin-2-onedihydrochloride a) 4-(4-Chlorophenethyl)piperazin-2-one

Piperazinone (1.04 g, 10.4 mmol), 1-chloro-4-(2-chloroethyl)benzene(2.28 g, 10.4 mmol) and K₂CO₃ (1.72 g, 12.4 mmol) were combined in DMSO(12 mL) and heated to 85° C. for 2 h. The mixture was partitionedbetween H₂O (20 mL) and CH₂Cl₂ (20 mL), and the organic layer wasremoved. The aqueous layer was extracted with CH₂Cl₂ (3×20 mL), thecombined organics were concentrated, and the residue was dissolved in 2N HCl (50 mL). This acidic mixture was washed with CH₂Cl₂ (3×20 mL) andthen made basic with 6 N NaOH. The basic mixture was extracted withCH₂Cl₂ (3×20 mL), and the extracts were combined, dried and concentratedto provide the title compound (1.51 g, 60%) as an orange solid: ¹H NMR(500 MHz, DMSO-d₆) δ 7.72 (s, 1H), 7.32 (d, J=8.8 Hz, 2H), 7.26 (d,J=8.8 Hz, 2H), 3.14-3.10 (m, 2H), 2.96 (s, 2H), 2.74 (t, J=6.6 Hz, 2H),2.62-2.53 (m, 4H).

b)4-(4-Chlorophenethyl)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)piperazin-2-onedihydrochloride

A suspension of 4-(4-chlorophenethyl)piperazin-2-one (90 mg, 0.38 mmol),tert-butyl8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate(130 mg, 0.344 mmol), Cs₂CO₃ (123 mg, 0.378 mmol), CuI (131 mg, 0.688mmol) and trans-1,2-bis(methylamino)cyclohexane (24 mg, 0.17 mmol) indioxane (10 mL) was degassed by bubbling N₂ through the suspension for45 min. The suspension was put under N₂ and heated at reflux for 5 d.The suspension was cooled, 9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH (10 mL) wasadded, and the resulting suspension was stirred at 25° C. for 30 min.The suspension was passed through a plug of silica gel, and the filtratewas washed with brine. Activated carbon was added to the resultingsolution, and the resulting suspension was filtered. The filtrate wasdried over Na₂SO₄ and concentrated under reduced pressure. Flashchromatography on silica gel (Et₂O/(8:1.9:0.1 Et₂O/MeOH/NH₄OH) affordedtert-butyl8-(4-(4-chlorophenethyl)-2-oxopiperazin-1-yl)-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylateas a tan solid. 2 N HCl in Et₂O (100 mL) was added to a solution of thetan solid in CH₂Cl₂ (5 mL) under N₂, and the resulting suspension wasstirred at 25° C. for 16 h. The suspension was concentrated, and theresulting residue was dissolved in MeOH (1 mL). Et₂O (100 mL) was added,the resulting suspension was filtered, and the solid was washed withEt₂O and put in a vacuum oven at 40° C. for 1 h to afford 22 mg (13%) ofthe title compound as a tan solid: ¹H NMR (500 MHz, DMSO-d₆) δ 11.54 (brs, 1H), 9.16 (br s, 2H), 7.54-7.32 (m, 6H), 6.96 (d, J=8.0 Hz, 1H),4.21-3.44 (m, 9H), 3.42-3.05 (m, 12H); ESI MS m/z 437 [M+H]⁺.

Example 54 Preparation of1-(3-Acetyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-(benzyloxy)pyridin-2(1H)-one

AcCl (0.03 mL, 0.4 mmol) was added to a solution of4-(benzyloxy)-1-(1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-onehydrochloride (102 mg, 0.242 mmol), DMAP (6 mg, 0.05 mmol) and Et₃N(0.10 mL, 0.73 mmol) in CH₂Cl₂ (10 mL) under N₂, and the resultingsolution was stirred at 25° C. for 4 h. The solution was concentratedunder reduced pressure. Flash chromatography on silica gel(Et₂O/(8:1.9:0.1 Et₂O/MeOH/NH₄OH) afforded 35 mg (34%) of the titlecompound as an off-white solid: mp 250-254° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 10.99 (s, 1H), 7.54 (d, J=7.5 Hz, 1H), 7.49-7.35 (m, 6H),7.19 (dd, J=2.5, 2.5 Hz, 1H), 6.88-6.83 (m, 1H), 6.07 (dd, J=8.0, 2.5Hz, 1H), 5.95 (d, J=2.5, 1H), 5.14 (s, 2H), 3.76-3.65 (m, 4H), 3.06-3.02(m, 1H), 2.97-2.91 (m, 2H), 2.87-2.82 (m, 1H), 2.12 (s, 3H); ESI MS m/z428 [M+H]⁺.

Example 55 Preparation of4-(4-Chloro-2-fluorobenzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-onehydrochloride

a) 4-(4-Chloro-2-fluorobenzyloxy)pyridin-2(1H)-one

A suspension of (4-chloro-2-fluorophenyl)methanol (3.24 g, 20.1 mmol),2-chloro-4-iodopyridine (4.40 g, 18.3 mmol), Cs₂CO₃ (7.76 g, 23.8 mmol),CuI (3.48 g, 18.7 mmol) and 1,10-phenanthroline (659 mg, 3.66 mmol) intoluene (20 mL) was degassed by bubbling N₂ through the suspension for15 min. The suspension was put under N₂ and heated at 105° C. for 18 h.The suspension was cooled, 9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH (10 mL) wasadded, and the resulting suspension was passed through a plug of SiO₂.The resulting solution was concentrated under reduced pressure. Flashchromatography on silica gel (hexanes/(1:1 EtOAc/hexanes), 100:0 to0:100) afforded a white solid. A suspension of the white solid andNH₄OAc (2.66 g, 34.6 mmol) in 1:1 HCO₂H/H₂O (20 mL) was heated at refluxwith stirring for 4 d. The solution was cooled and concentrated underreduced pressure. The resulting residue was made basic with saturatedNaHCO₃ solution, and the resulting suspension was filtered. The solidwas washed with H₂O and CH₂Cl₂, and dried under reduced pressure toafford 1.28 g (28%) of the title compound as a white solid: ¹H NMR (300MHz, DMSO-d₆) δ 11.14 (br s, 1H), 7.59 (dd, J=8.1, 8.1 Hz, 1H), 7.52(dd, J=10.2, 1.8 Hz, 1H), 7.36 (dd, J=8.1, 1.8 Hz, 1H), 7.25 (d, J=7.2Hz, 1H), 5.89 (d, J=7.2, 2.4 Hz, 1H), 5.83 (d, J=2.4 Hz, 1H), 5.06 (s,2H).

b)4-(4-Chloro-2-fluorobenzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-onehydrochloride

A suspension of 4-(4-chloro-2-fluorobenzyloxy)pyridin-2(1H)-one (87 mg,0.34 mmol), tert-butyl8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate(143 mg, 0.380 mmol), CuI (78 mg, 0.41 mmol), 8-hydroxyquinoline (10 mg,0.068 mmol) and Cs₂CO₃ (124 mg, 0.38 mmol) in DMSO (10 mL) was degassedunder reduced pressure for 45 min. The suspension was put under N₂ andstirred at 135° C. for 22 h. The suspension was cooled, 9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension wasstirred at 25° C. for 30 min. The suspension was passed through a plugof silica gel, and the filtrate was washed with brine. Activated carbonwas added to the resulting solution, and the resulting suspension wasfiltered. The filtrate was dried over Na₂SO₄, and concentrated underreduced pressure. Flash chromatography on silica gel (Et₂O/(8:1.9:0.1Et₂O/MeOH/NH₄OH) afforded an off-white powder. 2 N HCl in Et₂O (100 mL)was added to a solution of the yellow residue in CH₂Cl₂ (5 mL) under N₂,and the resulting suspension was stirred at 25° C. for 22 h. Thesuspension was filtered, and the solid was washed with Et₂O and put in avacuum oven at 40° C. for 2 h to afford 48 mg (29%) of the titlecompound as a white powder: ¹H NMR (500 MHz, DMSO-d₆) δ 9.21 (br s, 2H),7.63 (dd, J=8.0, 8.0 Hz, 1H), 7.57-7.50 (m, 3H), 7.43 (d, J=1.5 Hz, 1H),7.39 (dd, J=8.5, 2.0 Hz, 1H), 6.95 (dd, J=8.5, 2.0 Hz, 1H), 6.08 (dd,J=7.5, 3.0 Hz, 1H), 6.02 (d, J=2.5 Hz, 1H), 5.18 (s, 2H), 3.69 (s, 3H),3.41-3.31 (m, 4H), 3.28-3.22 (m, 2H), 3.16-3.09 (m, 2H); ESI MS m/z 452[M+H]⁺.

Example 56 Preparation of4-((3,5-Dichloropyridin-2-yl)methoxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-onehydrochloride

a) 3,5-Dichloro-2-((2-chloropyridin-4-yloxy)methyl)pyridine

(3,5-Dichloropyridin-2-yl)methanol (2.00 g, 10.4 mmol),2-chloro-4-iodopyridine (2.49 g, 10.4 mmol), cesium carbonate (4.41 g,13.5 mmol), CuI (1.97 g, 10.4 mmol) and 1,10-phenanthroline (374 mg,2.08 mmol) were stirred in toluene (20 mL) and degassed with a nitrogenstream for 10 minutes. The mixture was heated to 105° C. for 16 h,allowed to cool and filtered through a silica plug eluting with ethylacetate. The filtrate was concentrated, and the resulting residue waspurified by column chromatography (80 g ISCO column column eluting withethyl acetate/hexanes; gradient 100% hexanes to 40% ethyl acetate) toprovide the title compound (1.15 g, 38%) as an orange solid: ¹H NMR (300MHz, CDCl₃) δ 8.50 (d, J=2.1 Hz, 1H), 8.21 (d, J=5.8 Hz, 1H), 7.80 (d,J=2.1 Hz, 1H), 6.97 (d, J=2.2 Hz, 1H), 6.88-6.85 (dd, J=5.8, 2.2 Hz,1H), 5.31 (s, 2H).

b) 4((3,5-Dichloropyridin-2-Amethoxy)pyridin-2(1H)-one

3,5-Dichloro-2-((2-chloropyridin-4-yloxy)methyl)pyridine (1.15 g, 4.03mmol) and ammonium acetate (1.55 g, 20.0 mmol) were heated to 110° C. ina mixture of formic acid (20 mL) and water (20 mL) for 5 days. Themixture was concentrated to remove most of the liquid and then adjustedto pH 8 with NaHCO₃ solution. The solid was filtered off to provide thetitle compound (910 mg, 82%) as a tan solid: ¹H NMR (300 MHz, DMSO-d₆) δ11.1 (br s, 1H), 8.66 (d, J=2.1 Hz, 1H), 8.34 (d, J=2.1 Hz, 1H), 7.25(d, J=7.3 Hz, 1H), 5.90-5.87 (dd, J=7.3, 2.8 Hz, 1H), 5.82 (d, J=2.6 Hz,1H), 5.20 (s, 2H).

c)4((3,5-Dichloropyridin-2-yl)methoxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-onehydrochloride

A suspension of 4-((3,5-dichloropyridin-2-yl)methoxy)pyridin-2(1H)-one(103 mg, 0.380 mmol), tert-butyl8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate(131 mg, 0.345 mmol), Cs₂CO₃ (124 mg, 0.380 mmol), CuI (79 mg, 0.41mmol) and trans-1,2-bis(methylamino)cyclohexane (33 mg, 0.23 mmol) intoluene (10 mL) was degassed by bubbling N₂ through the suspension for45 min. The suspension was put under N₂ and heated at reflux for 2 d.The suspension was cooled, 9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH (10 mL) wasadded, and the resulting suspension was stirred at 25° C. for 30 min.The suspension was passed through a plug of silica gel, and the filtratewas washed with brine. Activated carbon was added to the resultingsolution, and the resulting suspension was filtered. The filtrate wasdried over Na₂SO₄ and concentrated under reduced pressure. Flashchromatography on silica gel (Et₂O/(8:1.9:0.1 Et₂O/MeOH/NH₄OH) affordeda viscous oil. 2 N HCl in Et₂O (100 mL) was added to a solution of theviscous oil in CH₂Cl₂ (10 mL) under N₂, and the resulting suspension wasstirred at 25° C. for 16 h. The suspension was filtered, and the solidwas washed with Et₂O and put in a vacuum oven at 40° C. for 3 h toafford 59 mg (34%) of the title compound as a white powder: mp 178-180°C.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.14 (br s, 2H), 8.69 (s, 1H), 8.37 (s,1H), 7.55 (d, J=8.0 Hz, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.44 (s, 1H), 6.95(d, J=8.5 Hz, 1H), 6.09 (dd, J=7.5, 2.5 Hz, 1H), 6.01 (s, 1H), 5.30 (s,2H), 3.69 (s, 3H), 3.42-3.30 (m, 4H), 3.28-3.22 (m, 2H), 3.17-3.09 (m,2H); ESI MS m/z 469 [M+H]⁺.

Example 57 Preparation of4-(4-Fluorobenzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-onehydrochloride

a) 2-Chloro-4-(4-fluorobenzyloxy)pyridine (CAS Registry Number924311-93-3) (WO 2007/018248 to Ando et al., which is herebyincorporated by reference in its entirety)

A mixture of 2-chloro-4-iodopyridine (5.0 g, 21 mmol), 4-fluorobenzylalcohol (2.51 mL, 23.0 mmol), cesium carbonate (8.9 g, 27 mmol), CuI(4.0 g, 21 mmol) and phenanthronine (0.76 g, 4.2 mmol) in toluene (20mL) was purged with nitrogen for 10 min. The reaction mixture was heatedat 105° C. overnight. The resulting mixture was cooled, diluted withEtOAc, and the resulting solution was washed with brine, passed througha pad of celite and concentrated under reduced pressure. The resultingresidue was purified by flash column chromatography (hexanes/EtOAc 100%to 85%) to give the title compound as a mixture with 4-fluorobenzylalcohol (3.9 g, mixture), which was used in next step without furtherpurification: ¹H NMR (500 MHz, CDCl₃) δ 8.20 (d, J=6.0 Hz, 1H), 7.38(dd, J=8.5, 5.5 Hz, 2H), 7.10 (t, J=8.5 Hz, 2H), 6.90 (d, J=2.0 Hz, 1H),6.80 (dd, J=5.5, 2.0 Hz, 1H), 5.06 (s, 2H).

b) 4-(4-Fluorobenzyloxy)pyridin-2(1H)-one (CAS Registry Number586373-38-8) (WO 2003/068230 to Devadas et al., which is herebyincorporated by reference in its entirety)

A mixture of 2-chloro-4-(4-fluorobenzyloxy)pyridine (3.9 g, mixture) andammonium acetate (4.2 g, 55 mmol) in formic acid (20 mL, 90% in water)and water (20 mL) was heated under reflux for 6 days. The resultingmixture was concentrated under reduced pressure, triturated with EtOAcand filtered. The resulting filtrate was concentrated under reducedpressure and purified by flash column chromatography (hexanes/EtOAc 17%to 50%; then DCM/MeOH/concentrated ammonia 80:18:2) to give the titlecompound (0.80 g, 17%) as an off-white solid: ¹H NMR (500 MHz, CDCl₃) δ12.61-2.32 (br s, 1H), 7.38 (dd, J=8.5, 5.5 Hz, 2H), 7.22 (d, J=7.5 Hz,1H), 7.09 (t, J=8.5 Hz, 2H), 6.03 (dd, J=7.5, 2.5 Hz, 1H), 5.95 (d,J=2.5 Hz, 1H), 4.98 (s, 2H).

c) tert-Butyl8-(4-(4-fluorobenzyloxy)-2-oxopyridin-1(2H)-yl)-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)carboxylate

A suspension of 4-(4-fluorobenzyloxy)pyridin-2(1H)-one (79 mg, 0.36mmol), tert-butyl8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate(150 mg, 0.40 mmol), 8-hydroxyquinoline (11 mg, 0.072 mmol) and Cs₂CO₃(129 mg, 0.40 mmol) in DMSO (10 mL) was degassed under reduced pressurefor 40 min. CuI (82 mg, 0.43 mmol) was added to the above solution, andthe reaction mixture was degassed under reduced pressure for 2×5 min.The suspension was cooled, 9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH (10 mL) wasadded, and the resulting suspension was stirred at 25° C. for 5 min.Celite was added, and the suspension was stirred for 5 min. Thesuspension was filtered through Celite, and the filtrate was washed withbrine. The resulting solution was dried over Na₂SO₄ and concentratedunder reduced pressure. Purification by preparative TLC(DCM/MeOH/concentrated ammonia 98:1.8:0.2) gave partially purifiedproduct, which was dissolved in DCM and stirred with charcoal for 10min. The suspension was filtered, and the filtrate was concentratedunder reduced pressure to afford the title compound (0.12 g, 64%) as ayellow solid: ¹H NMR (500 MHz, CDCl₃) δ 7.52 (t, J=8.0 Hz, 1H), 7.41(dd, J=8.5, 5.5 Hz, 2H), 7.31 (d, J=7.5 Hz, 1H), 7.24 (s, 1H), 7.10 (t,J=8.5 Hz, 2H), 7.00 (d, J=8.5 Hz, 1H), 6.07 (s, 1H), 6.02 (dd, J=7.5,2.0 Hz, 1H), 5.01 (s, 2H), 3.78-3.63 (m, 4H), 3.64 (s, 3H), 3.05-2.98(m, 4H), 1.50-1.48 (m, 9H).

d)4-(4-Fluorobenzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-onehydrochloride

To a solution of tert-butyl8-(4-(4-fluorobenzyloxy)-2-oxopyridin-1(2H)-yl)-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate(120 mg, 0.23 mmol) in dichloromethane (1.0 mL) was added HCl (2M indiethyl ether, 5.0 mL). The resulting slurry was stirred at roomtemperature overnight and concentrated under reduced pressure to affordthe title compound (85 mg, 82%) as a yellow solid: ¹H NMR (500 MHz,CD₃OD) δ 7.59 (d, J=8.5 Hz, 2H), 7.50 (dd, J=8.0, 5.5 Hz, 2H), 7.40 (s,1H), 7.15 (t, J=8.5 Hz, 2H), 7.01 (d, J=8.5 Hz, 1H), 6.30 (t, J=6.5 Hz,1H), 6.14 (br s, 1H), 5.16 (s, 2H), 3.74 (s, 3H), 3.54 (t, J=5.5 Hz,2H), 3.48 (t, J=5.5 Hz, 2H), 3.34 (t, J=5.5 Hz, 2H), 3.24 (t, J=5.5 Hz,2H); ESI MS m/z 418 [M+H]⁺.

Example 58 Preparation of1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-2(1H)-onehydrochloride

a) 2-Methoxy-4-(6-(trifluoromethyl)pyridin-3-yl)pyrimidine

A solution of 4-chloro-2-methoxypyrimidine (0.50 g, 3.5 mmol),2-trifluoromethyl)pyridine-5-boronic acid (1.0 g, 5.2 mmol) andpotassium carbonate (0.95 g, 6.9 mmol) in DMSO was degassed with argonfor 10 min. 1,1′-Bis(diphenylphosphino)ferrocenedichloropalladium(II)(0.26 g, 0.35 mmol) was then added to the above solution. The reactionmixture was degassed with argon for 5 min and then heated at 100° C. for4 h. The reaction solution was cooled to room temperature, diluted withethyl acetate, washed with water (2×) and brine, dried over sodiumsulfate and concentrated under reduced pressure. The resulting residuewas purified by flash column chromatography (silica gel hexanes/ethylacetate 95:5 to 50:50) to afford the title compound (0.80 g, 90%) as anoff-white solid: ¹H NMR (500 MHz, CDCl₃) δ 9.37 (d, J=2.0 Hz, 1H), 8.69(d, J=5.5 Hz, 1H), 8.61 (dd, J=8.0, 2.0 Hz, 1H), 7.83 (d, J=8.5 Hz, 1H),7.44 (d, J=5.0 Hz, 1H), 4.12 (s 3H).

b) 4-(6-(Trifluoromethyl)pyridin-3-yl)pyrimidin-2(1H)-one

A solution of 2-methoxy-4-(6-(trifluoromethyl)pyridin-3-yl)pyrimidine(0.35 g, 1.37 mmol) in concentrated HCl (3.0 mL) was heated under refluxfor 16 h. The reaction solution was then cooled to 0° C., diluted withwater and basified with aqueous sodium hydroxide. The mixture was thenextracted with dichloromethane (2×), a 3:1 mixture of chloroform and2-propanol (3×), ethyl acetate (4×) and ethyl acetate with 5% methanol(3×). The combined organic extract was dried over sodium sulfate andconcentrated under reduced pressure to afford the title compound (0.25g, 75%) as a tan solid: ¹H NMR (500 MHz, CD₃OD) δ 9.34 (s, 1H), 8.67 (d,J=8.5 Hz, 1H), 8.20 (d, J=6.0 Hz, 1H), 7.93 (d, J=8.5 Hz, 1H), 7.08 (d,J=5.5 Hz, 1H).

c) tert-Butyl6-methyl-8-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-1(2H)-yl)-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate

A suspension of 4-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-2(1H)-one(69 mg, 0.29 mmol), tert-butyl8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate(120 mg, 0.32 mmol), 8-hydroxyquinoline (8.4 mg, 0.058 mmol) and Cs₂CO₃(110 mg, 0.35 mmol) in DMSO (5.0 mL) was degassed under reduced pressurefor 30 min. CuI (66.7 mg, 0.35 mmol) was then added to the abovesolution, and the reaction mixture was degassed under reduced pressurefor 5 min. The suspension was then stirred at 135° C. under nitrogenovernight. The suspension was cooled and diluted with ethyl acetate. Theresulting mixture was washed with aqueous LiCl (5%), ammonium hydroxide(2×), and brine. The organic extract was separated, dried over sodiumsulfate, and concentrated under reduced pressure. The resulting crudematerial was purified by preparative TLC (hexanes/ethyl acetate 1:1 thenDCM/MeOH 96:4). The desired band was collected and extracted withdichloromethane. The resulting solution was treated with charcoal,filtered through a pad of celite, and concentrated under reducedpressure to give the title compound (36 mg, 20%) as a yellow foam: ¹HNMR (500 MHz, CDCl₃) δ 9.36 (s, 1H), 8.76 (d, J=7.0 Hz, 1H), 8.99 (d,J=6.5 Hz, 1H), 7.86 (d, J=8.5 Hz, 1H), 7.58-7.56 (m, 1H), 7.38-7.37 (m,1H), 7.09-7.08 (m, 1H), 6.93 (d, J=7.0 Hz, 1H), 3.80-3.68 (m, 4H), 3.68(s, 3H), 3.09-2.99 (m, 4H), 1.49 (s, 9H).

d)1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-2(1H)-onehydrochloride

To a solution of tert-butyl6-methyl-8-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-1(2H)-yl)-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate(36 mg, 0.067 mmol) in dichloromethane (1.0 mL) was added HCl (2M indiethyl ether, 5.0 mL). The resulting slurry was stirred at roomtemperature for 14 h and then concentrated under reduced pressure. Theresulting residue was purified by semi-preparative HPLC (Phenomenex LunaC18 (2), 250.0×21.20 mm, 10 micron, H₂O with 0.05% TFA and CH₃CN with0.05% TFA). The clean fractions were combined, concentrated underreduced pressure and lypholized overnight. The trifluroacetate salt wasdissolved in a 1:2 mixture of acetonitrile and water (10 mL) and passedthrough a plug of SAX column. The column was further washed with a 1:2mixture of acetonitrile and water (10 mL). The combined filtrate waslypholized to give the title compound (30.1 mg, 94%) as a yellow solid:¹H NMR (500 MHz, CD₃OD) δ 9.48 (s, 1H), 8.80 (d, J=8.5 Hz, 1H), 8.38 (d,J=6.5 Hz, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.59 (d,J=1.0 Hz, 1H), 7.36 (d, J=7.0 Hz, 1H), 7.18 (dd, J=8.5, 1.5 Hz, 1H),3.78 (s, 3H), 3.56 (t, J=5.5 Hz, 2H), 3.50 (t, J=5.5 Hz, 2H), 3.37 (t,J=5.5 Hz, 2H), 3.26 (t, J=5.5 Hz, 2H); ESI MS m/z 440 [M+H]⁺.

Example 59 Preparation of1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(2-(pyridin-2-yl)ethyl)piperazin-2-onedihydrochloride

a) 2-(2-Chloroethyl)pyridine hydrochloride (CAS Registry Number4226-37-3) (U.S. Pat. No. 2,533,243 to Gump et al., which is herebyincorporated by reference in its entirety)

2-(Pyridin-2-yl)ethanol (7.2 g, 58 mmol) and thionyl chloride (10.6 g,89.1 mmol) were combined in THF (30 mL) and heated at reflux for 16 h.Upon cooling, the solid was filtered off and washed with THF to providethe title compound (4.2 g, 40%) as an off-white solid: ¹H NMR (300 MHz,DMSO-d₆) δ 8.82 (d, J=5.6 Hz, 1H), 8.51-8.45 (dt, J=7.8, 1.5 Hz, 1H),8.00 (d, J=7.9 Hz, 1H), 7.91-7.86 (m, 1H), 4.14 (t, J=6.5 Hz, 2H),3.53(t, J=6.5 Hz, 2H).

b) 4-(2-(Pyridin-2-yl)ethyl)piperazin-2-one

Piperazinone (2.2 g, 22 mmol), 2-(2-chloroethyl)pyridine hydrochloride(3.9 g, 22 mmol) and i-Pr₂NEt (5.67 g, 7.6 mL, 44 mmol) were heated atreflux for 16 h. The mixture was concentrated, and the residue waspurified by column chromatography (80 g ISCO column eluting withmethylene chloride and a 10:1 methanol/ammonium hydroxide mixture;gradient 100% methylene chloride to 90% methylene chloride) to providethe title compound (1.5 g, 33%) as a yellow solid; ESI MS m/z 206[M+H]⁺.

c) tert-Butyl6-methyl-8-(2-oxo-4-(2-(pyridin-2-ypethyl)piperazin-1-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

tert-Butyl8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(200 mg, 0.528 mmol) and 4-(2-(pyridin-2-yl)ethyl)piperazin-2-one (118mg, 0.576 mmol) were reacted following the procedure for Example 53(step b) to provide the title compound (52 mg, 20%) as a white solid:ESI MS m/z 504 [M+H]⁻.

d)1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(2-(pyridin-2-yl)ethyl)piperazin-2-onedihydrochloride

tert-Butyl6-methyl-8-(2-oxo-4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(52 mg, 0.10 mmol) was reacted following the procedure for Example 53(step b) to provide the title compound (23 mg, 49%) as a white solid: ¹HNMR (500 MHz, CD₃OD) δ 8.86 (d, J=5.5 Hz, 1H), 8.49-8.46 (dt, J=7.9, 1.5Hz, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.90 (t, J=6.8 Hz, 1H), 7.60 (d, J=8.4Hz, 1H), 7.44 (d, J=1.5 Hz, 1H), 7.08 (dd, J=8.5, 2.0 Hz, 1H), 4.54 (s,2H), 4.13 (s, 2H), 4.09 (t, J=5.5 Hz, 2H), 3.80 (t, J=5.0 Hz, 2H), 3.75(s, 3H), 3.73 (t, J=5.0 Hz, 2H), 3.63-3.56 (m, 4H), 3.20-3.17 (m, 2H),2.13-2.09 (m, 2H); ESI MS m/z 404 [M+H]⁺; HPLC (Method C) 95.7% (AUC),t_(R)=10.15 min

Example 60 Preparation of2-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-5-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridazin-3(2H)-onehydrochloride ALB 139968(a)

a) tert-Butyl6-methyl-8-(6-oxo-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridazin-1(6H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

tert-Butyl8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(0.13 g, 0.34 mmol),5-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridazin-3(2H)-one (0.10 g,0.67 mmol), and Cs₂CO₃ (0.14 g, 0.44 mmol) were suspended in DMSO (2.0mL), and the air was removed under vacuum for 15 min. The system wasflushed with Ar, and 8-hydroxyquinoline (15 mg, 0.10 mmol) and copperiodide (0.16 g, 0.84 mmol) were added to the suspension. Theevacuation/Ar flushing process was repeated twice more, and the reactionmixture was heated at 110° C. for 48 h under N₂. The mixture was cooled,diluted with 5.0:3.5:1.5 NH₄C1(aq.)/NH₄OH/H₂O (30 mL), and the resultingsuspension was stirred at ambient temperature for 30 min. The resultingsolids were collected by filtration, dissolved in CH₂Cl₂ (30 mL) andwashed with 5.0:3.5:1.5 NH₄Cl (aq.)/NH₄OH/H₂O (40 mL) (2×20 mL). Theresulting organic solution was dried over Na₂SO₄, filtered andconcentrated to dryness under reduced pressure. Flash chromatography (12g ISCO column, CH₂Cl₂/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 4 columnvolumes, increased to 50:50 over 20 column volumes and held for 4 columnvolumes) gave the title compound (46 mg, 24%) as an orange film: ¹H NMR(500 MHz, DMSO-d₆) δ 8.92 (s, 1H), 8.23 (d, J=8.5 Hz, 1H), 8.01 (d,J=8.0 Hz, 1H), 7.99 (d, J=3.0 Hz, 1H), 7.48 (d, J=8.0 Hz, 2H), 7.05 (dd,J=8.5, 1.5 Hz, 1H), 6.56 (d, J=2.5 Hz, 1H), 5.41 (s, 2H), 4.59-4.57 (m,2H), 3.68-3.64 (m, 5H), 3.01-2.98 (m, 2H), 1.97-1.90 (m, 2H), 1.36-1.27(m, 9H).

b)2-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-54(6-(trifluoromethyppyridin-3-yl)methoxy)pyridazin-3(2H)-onehydrochloride

1.25 M HCl in MeOH (4.0 mL) was added to tert-butyl6-methyl-8-(6-oxo-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridazin-1(6H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(43 mg, 0.075 mmol), and the resulting solution was stirred under N₂ atambient temperature for 18 h. The solution was concentrated underreduced pressure, and the resulting residue was diluted with MeOH (1.0mL) and Et₂O (10 mL). The resulting solids were collected by filtrationto provide the title compound (23 mg, 61%) as an off-white solid: ¹H NMR(500 MHz, DMSO-d₆) δ 8.91 (d, J=1.5 Hz, 1H), 8.87 (s, 2H), 8.22 (dd,J=8.5, 1.5 Hz, 1H), 8.02-8.00 (m, 2H), 7.64 (d, J=8.5 Hz, 1H), 7.57 (d,J=1.5 Hz, 1H), 7.13 (dd, J=8.5, 2.0 Hz, 1H), 6.56 (d, J=3.0 Hz, 1H),5.41 (s, 2H), 4.44 (s, 2H), 3.72 (s, 3H), 3.47-3.43 (m, 2H), 3.10 (t,J=5.5 Hz, 2H), 2.08-2.04 (m, 2H); ESI MS m/z 470 [M+H]⁺; HPLC (MethodA) >99% (AUC), t_(R)=14.1 min.

Example 61 Preparation of1-(2-Acetyl-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-((5fluoropyridin-2-yl)methyoxy)pyridin-2(1H)-one

Triethylamine (48 μL, 0.34 mmol), DMAP (4.0 mg, 0.034 mmol) and acetylchloride (18 μL, 0.26 mmol) were added to a solution of4-((5-fluoropyridin-2-yl)methoxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-onehydrochloride (78 mg, 0.17 mmol) in CH₂Cl₂ (10 mL), and the resultingsolution was stirred at ambient temperature for 3 h under N₂. Theresulting solution was concentrated to dryness under reduced pressure.Flash chromatography (12 g ISCO column, CH₂Cl₂/(80:18:2CH₂Cl₂/MeOH/NH₄OH), 100:0 for 2 column volumes, increased to 50:50 over20 column volumes and held for 1 column volume, then increased to 0:100over 10 column volumes and held for 12 column volumes) gave the titlecompound (55 mg, 70%) as an off-white solid: mp 78-83° C.; ¹H NMR (500MHz, DMSO-d₆) δ 8.62 (d, J=3.0 Hz, 1H), 7.83 (ddd, J=8.5, 8.5, 3.0 Hz,1H), 7.66-7.49 (m, 3H), 7.39 (dd, J=21.0, 2.0 Hz, 1H), 6.93 (ddd,J=22.5, 8.0, 1.5 Hz, 1H), 6.11 (dd, J=7.5, 2.5 Hz, 1H), 5.96 (dd, J=5.0,3.0 Hz, 1H), 5.21 (s, 2H), 4.69-4.68 (m, 2H), 3.78-3.75 (m, 2H),3.67-3.65 (m, 3H), 3.03-2.96 (m, 2H), 2.09-1.90 (m, 5H); ESI MS m/z 461[M+H]⁻; HPLC (Method A) 98.7% (AUC), t_(R)=16.0 min.

Example 62 Preparation of1-(2-Acetyl-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one

Triethylamine (58 μL, 0.41 mmol), DMAP (5.0 mg, 0.041 mmol) and acetylchloride (22 μL, 0.31 mmol) were added to a solution of1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-onehydrochloride (97 mg, 0.21 mmol) in CH₂Cl₂ (15 mL), and the resultingsolution was stirred at ambient temperature for 18 h under N₂. Theresulting solution was concentrated to dryness under reduced pressure.Flash chromatography (12 g ISCO column, CH₂Cl₂/(80:18:2CH₂Cl₂/MeOH/NH₄OH), 100:0 for 2 column volumes, increased to 50:50 over20 column volumes and held for 1 column volume, then increased to 0:100over 10 column volumes and held for 12 column volumes) gave the titlecompound (58 mg, 59%) as a yellow powder: mp 156-162° C.; ¹H NMR (500MHz, DMSO-d₆) δ 9.19 (s, 1H), 8.49 (dd, J=8.0, 2.0 Hz, 1H), 8.05 (d,J=8.0 Hz, 1H), 7.88-7.83 (m, 1H), 7.72-7.49 (m, 2H), 7.07-6.99 (m, 2H),6.80-6.78 (m, 1H), 4.72-4.70 (m, 2H), 3.79-3.76 (m, 2H), 3.69-3.68 (m,3H), 3.05-2.98 (m, 2H), 2.02-1.90 (m, 5H); ESI MS m/z 481 [M+H]⁺; HPLC(Method A) >99% (AUC), t_(R)=18.1 min.

Example 63 Preparation of4-((5-Chloropyridin-2-yl)methoxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-onehydrochloride

a) tert-Butyl8-(4-((5-chloropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (300 mg, 0.792 mmol) and4-((5-chloropyridin-2-yl)methoxy)pyridin-2(1H)-one (187 mg, 0.792 mmol)were reacted following the procedure for Example 2 (step d) to providethe title compound (130 mg, 30%) as a yellow oil: ESI MS m/z 535 [M+H]⁺.

b)4-((5-Chloropyridin-2-yl)methoxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-onehydrochloride

tert-Butyl8-(4-((5-chloropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(130 mg, 0.243 mmol) was reacted following the procedure for Example 2(step e) to provide the title compound (64 mg, 56%) as a yellow solid:mp 260-266° C.; ¹H NMR (500 MHz, CD₃OD) δ 8.59 (d, J=2.4 Hz, 1H),7.95-7.91 (dd, J=8.4, 2.4 Hz, 1H), 7.62-7.58 (m, 3H), 7.41 (d, J=1.6 Hz,1H), 7.05-7.04 (dd, J=8.4, 1.6 Hz, 1H), 6.34-6.30 (dd, J=7.6, 2.7 Hz,1H), 6.11 (d, J=2.7 Hz, 1H), 5.26 (s, 2H), 4.46 (s, 2H), 3.75 (s, 3H),3.53-3.49 (m, 2H), 3.19-3.17 (m, 2H), 2.19-2.12 (m, 2H); ESI MS m/z 435[M+H]⁺.; HPLC (Method B) >99% (AUC), t_(R)=12.2 min.

Example 64 Preparation of4-(4-Chlorophenethyl)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)piperazin-2-onehydrochloride

a) tert-Butyl8-(4-(4-chlorophenethyl)-2-oxopiperazin-1-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

tert-Butyl8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(250 mg, 0.66 mmol) and 4-(4-chlorophenethyl)piperazin-2-one (157 mg,0.66 mmol) were reacted following the procedure for Example 53 (step b)to provide the title compound (250 mg, 70%) as a colorless oil: ESI MSm/z 537 [M+H]⁺.

b)4-(4-Chlorophenethyl)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)piperazin-2-onehydrochloride

tert-Butyl8-(4-(4-chlorophenethyl)-2-oxopiperazin-1-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(250 mg, 0.465 mmol) was reacted following the procedure for Example 53(step b) to provide the title compound (116 mg, 53%) as a white solid:mp 252-257° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.14-8.91 (s, 2H), 7.57 (d,J=8.7 Hz, 1H), 7.40-7.30 (m, 5H), 6.98 (d, J=8.4 Hz, 1H), 4.42-4.35 (m,2H), 3.79-3.69 (m, 5H), 3.46-3.36 (m, 2H), 3.26-3.18 (m, 2H), 3.10-3.02(m, 2H), 2.97-2.76 (m, 4H), 2.72-2.61 (m, 2H), 2.10-1.97 (m, 2H); ESI MSm/z 437 [M+H]⁺; HPLC (Method B) 97.5% (AUC), t_(R)=10.9 min.

Example 65 Preparation of4-(2,4-Dichlorobenzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-onehydrochloride

a) tert-Butyl8-(4-(2,4-dichlorobenzyloxy)-2-oxopyridin-1(2H)-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

tert-Butyl8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(155 mg, 0.411 mmol) and 4-(2,4-dichlorobenzyloxy)pyridin-2(1H)-one (110mg, 0.411 mmol) were reacted following the procedure for Example 2 (stepd) to provide the title compound (105 mg, 45%) as a yellow foam: ESI MSm/z 568 [M+H]⁺.

b)4-(2,4-Dichlorobenzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-onehydrochloride

tert-Butyl8-(4-(2,4-dichlorobenzyloxy)-2-oxopyridin-1(2H)-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(105 mg, 0.184 mmol) was reacted following the procedure for Example 2(step e) to provide the title compound (36 mg, 38%) as a white solid: ¹HNMR (500 MHz, DMSO-d₆) δ 9.20-9.10 (s, 2H), 7.74 (d, J=2.1 Hz, 1H),7.68-7.63 (m, 2H), 7.56 (d, J=7.6 Hz, 1H), 7.52-7.51 (dd, J=8.2, 2.0 Hz,1H), 7.49 (d, J=1.6 Hz, 1H), 7.01-6.98 (dd, J=8.4, 1.8 Hz, 1H),6.12-6.09 (dd, J=7.6, 2.7 Hz, 1H), 6.01 (d, J=2.7 Hz, 1H), 5.19 (s, 2H),4.46-4.39 (s, 2H), 3.71 (s, 3H), 3.47-3.30 (m, 2H), 3.14-3.03 (m, 2H),2.12-1.99 (m, 2H); ESI MS m/z 468 [M+H]⁺; HPLC (Method B) 97.1% (AUC),t_(R)=14.4 min.

Example 66 Preparation of4-(2,4-Difluorobenzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-onehydrochloride

a) tert-Butyl 8-(4-(2,4-difluorobenzyloxy)-2-oxopyridin-1(2H)-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(155 mg, 0.411 mmol) and 4-(2,4-difluorobenzyloxy)pyridin-2(1H)-one (97mg, 0.41 mmol) was reacted following the procedure for Example 2 (stepd) to provide the title compound (130 mg, 59%) as a green oil: ESI MSm/z 536 [M+H]⁺.

b)4-(2,4-Difluorobenzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

tert-Butyl8-(4-(2,4-difluorobenzyloxy)-2-oxopyridin-1(2H)-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)carboxylate (130 mg, 0.242 mmol) was reacted following the procedure forExample 2 (step e) to provide the title compound (54 mg, 47%) as a whitesolid: mp 272-280° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.14-8.77 (s, 2H),7.69-7.63 (m, 2H), 7.55 (d, J=7.5 Hz, 1H), 7.48 (d, J=1.8 Hz, 1H),7.37-7.32 (dt, J=10.3, 2.5 Hz, 1H), 7.19-7.15 (m, 1H), 7.01-6.99 (dd,J=8.3, 1.8 Hz, 1H), 6.08-6.06 (dd, J=7.5, 2.8 Hz, 1H), 6.04 (d, J=2.8Hz, 1H), 5.15 (s, 2H), 4.55-4.24 (m, 2H), 3.72 (s, 3H), 3.50-3.41 (m,2H), 3.10-3.08 (m, 2H), 2.14-1.91 (m, 2H); ESI MS m/z 436 [M+H]⁺; HPLC(Method B) >99% (AUC), t_(R)=13.3 min.

Example 67 Preparation of4-((3,5-Dichloropyridin-2-yl)methoxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-onedihydrochloride

a) tert-Butyl8-(4-((3,5-dichloropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)carboxylate

tert-Butyl8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(150 mg, 0.396 mmol) and4-((3,5-dichloropyridin-2-yl)methoxy)pyridin-2(1H)-one (107 mg, 0.396mmol) were reacted following the procedure for Example 2 (step d) toprovide the title compound (150 mg, 66%) as a green oil: ESI MS m/z 569[M+H]⁺.

d)4-((3,5-Dichloropyridin-2-yl)methoxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-onedihydrochloride

tert-Butyl8-(4-((3,5-dichloropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(150 mg, 0.263 mmol) was reacted following the procedure for Example 2(step e) to provide the title compound (102 mg, 71%) as a white solid:mp 251-256° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.21-8.98 (s, 2H), 8.69 (d,J=2.1 Hz, 1H), 8.37 (d, J=2.1 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.55 (d,J=7.6 Hz, 1H), 7.49 (d, J=1.8 Hz, 1H), 7.01-6.99 (dd, J=8.8, 1.8 Hz,1H), 6.10-6.09 (dd, J=7.6, 2.8 Hz, 1H), 6.01 (d, J=2.8 Hz, 1H), 5.30 (s,2H), 4.43-4.42 (m, 2H), 3.71 (s, 3H), 3.48-3.39 (m, 2H), 3.10-3.07 (m,2H), 2.14-1.93 (m, 2H); ESI MS m/z 469 [M+H]⁺; HPLC (Method B) >99%(AUC), t_(R)=12.9 min.

Example 68 Preparation of4-(4-Chloro-2-fluorobenzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-onehydrochloride

a) tert-Butyl 8-(4-(4-chloro-2-fluorobenzyloxy)-2-oxopyridin-1(2H)-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)carboxylate

tert-Butyl8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(150 mg, 0.400 mmol) and 4-(4-chloro-2-fluorobenzyloxy)pyridin-2(1H)-one(101 mg, 0.400 mmol) were reacted following the procedure for Example 2(step d) to provide the title compound (107 mg, 48%) as a yellow oil:ESI MS m/z 552 [M+H]⁺.

b)-(4-Chloro-2-fluorobenzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-onehydrochloride

tert-Butyl8-(4-(4-chloro-2-fluorobenzyloxy)-2-oxopyridin-1(2H)-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(107 mg, 0.194 mmol) was reacted following the procedure for Example 2(step e) to provide the title compound (59.9 mg, 63%) as a white solid:mp 191-200° C. deliquesc; ¹H NMR (500 MHz, DMSO-d₆) δ 9.22-9.04 (s, 2H),7.65-7.61 (m, 2H), 7.57-7.53 (m, 2H), 7.48 (d, J=1.8 Hz, 1H), 7.39-7.37(dd, J=8.1, 1.8 Hz, 1H), 7.00-6.97 (dd, J=8.2, 1.8 Hz, 1H), 6.09-6.07(dd, J=7.6, 2.8 Hz, 1H), 6.03 (d, J=2.8 Hz, 1H), 5.17 (s, 2H), 4.43-4.41(m, 2H), 3.71 (s, 3H), 3.38-3.33 (m, 2H), 3.18-3.08 (m, 2H), 2.10-2.06(m, 2H); ESI MS m/z 452 [M+H]⁺; HPLC (Method B) >96.3% (AUC), t_(R)=14.0min.

Example 69 Preparation of1-(2,6-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(6-(trffluoromethyl)pyridazin-3-yl)pyridin-2(1H)-onehydrochloride

1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one(34 mg, 0.078 mmol) was reacted following the procedure for Example 29to provide the title compound (34 mg, 89%) as an orange solid: ¹H NMR(500 MHz, DMSO-d₆) δ 10.14 (s, 1H), 8.71 (d, J=8.9 Hz, 1H), 8.47 (d,J=9.1 Hz, 1H), 7.92 (d, J=7.2 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.65 (d,J=1.7 Hz, 1H), 7.38 (d, J=1.8 Hz, 1H), 7.18-7.17 (dd, J=7.2, 2.0 Hz,1H), 7.15-7.14 (dd, J=8.4, 1.8 Hz, 1H), 4.76 (d, J=14.3 Hz, 1H),4.54-4.50 (dd, J=14.5, 6.5 Hz, 1H), 3.75 (s, 3H), 3.70-3.64 (m, 1H),3.46-3.40 (m, 1H), 3.16-3.05 (m, 2H), 2.81 (d, J=5.0 Hz, 3H), 2.20-2.14(m, 1H), 2.09-2.00 (m, 1H); ESI MS m/z 454 [M+H]⁺; HPLC (Method B) 97%(AUC), t_(R)=12.4 min.

Example 70 Preparation of1-(2,6-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-onehydrochloride

4-((5-Fluoropyridin-2-yl)methoxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one(200 mg, 0.478 mmol) was reacted following the procedure for Example 29to provide the title compound (201 mg, 90%) as a white solid: ¹H NMR(500 MHz, CD₃OD) δ 8.63 (d, J=2.7 Hz, 1H), 7.90-7.88 (dd, J=8.1, 2.8 Hz,1H), 7.81-7.79 (m, 2H), 7.71 (d, J=8.4 Hz, 1H), 7.51 (d, J=1.7 Hz, 1H),7.11-7.09 (dd, J=8.4, 1.8 Hz, 1H), 6.57-6.55 (dd, J=7.5, 2.8 Hz, 1H),6.34 (d, J=2.8 Hz, 1H), 5.39 (s, 2H), 4.80 (d, J=14.8 Hz, 1H), 4.59 (d,J=14.8 Hz, 1H), 3.85-3.75 (m, 4H), 3.56-3.51 (m, 1H), 3.26-3.15 (m, 2H),2.79 (s, 3H), 2.57-2.31 (m, 1H), 2.19-2.14 (m, 1H); ESI MS m/z 433[M+H]⁺; HPLC (Method B) 98.8% (AUC), t_(R)=11.7 min.

Example 71 Preparation of1-(2,6-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-((6-(trffluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-onehydrochloride

1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-one(64 mg, 0.14 mmol) was reacted following the procedure for Example 29 toprovide the title compound (30 mg, 42%) as a white solid: ¹H NMR (500MHz, DMSO-d₆) δ 10.52-10.04 (s, 1H), 8.88 (d, J=1.3 Hz, 1H), 8.20-8.18(dd, J=8.1, 1.5 Hz, 1H), 7.99 (d, J=8.1 Hz, 1H), 7.69 (d, J=8.2 Hz, 1H),7.60 (d, J=7.6 Hz, 1H), 7.50 (d, J=1.8 Hz, 1H), 7.02-7.00 (dd, J=8.6,1.8 Hz, 1H), 6.16-6.14 (dd, J=7.6, 2.8 Hz, 1H), 6.02 (d, J=2.8 Hz, 1H),5.35 (s, 2H), 4.72 (d, J=14.2 Hz, 1H), 4.51-4.47 (dd, J=14.6, 6.5 Hz,1H), 3.72 (s, 3H), 3.70-3.61 (m, 1H), 3.44-3.38 (m, 1H), 3.11-3.04 (m,2H), 2.79 (d, J=4.9 Hz, 3H), 2.17-2.14 (m, 1H), 2.06-2.03 (m, 1H); ESIMS m/z 483 [M+H]⁺; HPLC (Method B) 98.6% (AUC), t_(R)=13.1 min.

Example 72 Preparation of1-(2-Cyclobutyl-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-onehydrochloride

4-((5-Fluoropyridin-2-yl)methoxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one(300 mg, 0.717 mmol) was reacted following the procedure for Example 86to provide the title compound (270 mg, 74%) as a a white solid: mp260-265° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 11.0-10.35 (s, 1H), 8.61 (d,J=2.9 Hz, 1H), 7.85-7.81 (dt, J=8.8, 2.9 Hz, 1H), 7.66-7.63 (m, 2H),7.58 (d, J=7.6 Hz, 1H), 7.50 (d, J=1.7 Hz, 1H), 7.01-6.99 (dd, J=8.4,1.9 Hz, 1H), 6.14-6.12 (dd, J=7.6, 1.8 Hz, 1H), 5.96 (d, J=2.8 Hz, 1H),5.22 (s, 2H), 4.51 (d, J=14.2 Hz, 1H), 4.14-4.12 (dd, J=14.4, 5.2 Hz,1H), 3.72 (s, 3H), 3.67-3.62 (m, 1H), 3.56-3.52 (m, 1H), 3.30-3.25 (m,1H), 3.12-3.10 (m, 2H), 2.43-2.39 (m, 1H), 2.29-2.25 (m, 1H), 2.15-2.04(m, 4H), 1.70-1.68 (m, 1H), 1.62-1.68 (m, 1H); ESI MS m/z 473 [M+H]⁺;HPLC (Method B) >99% (AUC), t_(R)=12.4 min.

Example 73 Preparation of1-(2-Ethyl-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-onehydrochloride

4-((5-Fluoropyridin-2-yl)methoxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-one(200 mg, 0.478 mmol) was reacted following the procedure for Example 30to provide the title compound (23 mg, 10%) as a white solid: ¹H NMR (500MHz, DMSO-d₆) δ 10.00-9.95 (s, 1H), 8.62 (s, 1H), 7.85-7.80 (dt, J=8.8,3.0 Hz, 1H), 7.66-7.64 (m, 2H), 7.58 (d, J=7.6 Hz, 1H), 7.48 (s, 1H),7.00 (d, J=8.0 Hz, 1H), 6.14-6.12 (dd, J=7.6, 2.2 Hz, 1H), 5.97 (d,J=2.8 Hz, 1H), 5.21 (s, 2H), 4.72-4.34 (m, 2H), 3.71 (s, 3H), 3.69-3.63(m, 2H), 3.14-2.68 (m, 4H). 2.16-1.95 (m, 2H), 1.39-1.15 (m, 3H); ESI MSm/z 447 [M+H]⁺; HPLC (Method B) >99% (AUC), t_(R)=12.0 min.

Example 74 Preparation of1-(2,6-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(4-fluorophenethyl)piperazin-2-onehydrochloride a) 4-(4-Fluorophenethyl)piperazin-2-one

Piperazinone (1.20 g, 12.1 mmol), 1-fluoro-4-(2-chloroethyl)benzene(2.45 g, 12.1 mmol) and i-Pr₂NEt (3.25 g, 4.5 ml, 25 mmol) were combinedin acetonitrile (25 mL) and heated to 85° C. for 2 h. The mixture wasconcentrated and partitioned between H₂O (20 mL) and CH₂Cl₂ (20 mL), andthe organic layer was removed. The aqueous layer was extracted withCH₂Cl₂ (3×20 mL), the combined organics were concentrated, and theresidue was dissolved in 2 N HCl (50 mL). This acidic mixture was washedwith CH₂Cl₂ (3×20 mL) and then made basic with 6 N NaOH. The basicmixture was extracted with CH₂Cl₂ (3×20 mL), and the extracts werecombined, dried and concentrated to provide the title compound (1.30 g,48%) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ 7.18-7.13 (m, 2H),7.00-6.94 (m, 2H), 6.45 (s, 1H), 3.39-3.35 (m, 2H), 3.20 (s, 2H),2.78-2.62 (m, 6H).

b) tert-butyl8-(4-(4-fluorophenethyl)-2-oxopiperazin-1-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

tert-Butyl8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(514 mg, 1.356 mmol) and 4-(4-fluorophenethyl)piperazin-2-one (301 mg,1.356 mmol) were reacted following the procedure for Example 53 (step b)to provide the title compound (537 mg, 76%) as a white solid: ESI MS m/z521 [M+H]⁺.

c)4-(4-Fluorophenethyl)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)piperazin-2-one

tert-Butyl8-(4-(4-fluorophenethyl)-2-oxopiperazin-l-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(537 mg, mmol) was reacted following the procedure for Example 53 (stepb) to provide the title compound (447 mg, >100%) as a yellow foam: ESIMS m/z 421 [M+H]⁺.

d)1-(2,6-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(4-fluorophenethyl)piperazin-2-onehydrochloride)

4-(4-Fluorophenethyl)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)piperazin-2-one(100 mg, 0.238 mmol) was reacted following the procedure for Example 29to provide the title compound (53 mg, 24%) as a white solid: mp 211-220°C.; ¹H NMR (500 MHz, CD₃OD) δ 7.63 (d, J=8.0 Hz, 1H), 7.41 (s, 1H),7.34-7.32 (m, 2H), 7.08-7.04 (m, 3H), 4.75 (d, J=14.1 Hz, 1H), 4.54 (d,J=14.4 Hz, 1H), 4.00-3.85 (m, 2H), 3.80-3.70 (m, 5H), 3.60-3.47 (m, 2H),3.18-3.15 (m, 5H), 3.03-2.90 (m, 3H), 2.95 (s, 3H), 2.39-2.30 (m, 1H),2.20-2.15 (m, 1H); ESI MS m/z 435 [M+H]⁺; HPLC (Method B) >99% (AUC),t_(R)=10.4 min.

Example 75 Preparation of1-(2-Cyclobutyl-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(4-fluorophenethyl)piperazin-2-onehydrochloride

4-(4-Fluorophenethyl)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)piperazin-2-one(100 mg, 0.238 mmol) was reacted following the procedure for Example 86to provide the title compound (65 mg, 54%) as a white solid: mp 194-205°C.; ¹H NMR (500 MHz, CD₃OD) δ 7.58 (d, J=8.4 Hz, 1H), 7.40 (s, 1H),7.32-7.29 (m, 2H), 7.05-7.02 (m, 3H), 4.61 (d, J=14.6 Hz, 1H), 4.42 (d,J=14.6 Hz, 1H), 3.84-3.79 (m, 3H), 3.75 (s, 3H), 3.69-3.65 (m, 2H),3.63-3.34 (m, 3H), 3.42-2.78 (m, 7H), 2.51-2.38 (m, 1H), 2.38-2.25 (m,3H), 2.25-2.03 (m, 2H), 1.87-1.76 (m, 2H); ESI MS m/z 475 [M+H]⁺; HPLC(Method B) >99% (AUC), t_(R)=10.9 min.

Example 76 Preparation of1-(2-Ethyl-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(4-fluorophenethyl)piperazin-2-onehydrochloride

4-(4-Fluorophenethyl)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)piperazin-2-one(200 mg, 0.476 mmol) was reacted following the procedure for Example 30to provide the title compound (105 mg, 46%) as a white solid: mp190-205° C.; ¹H NMR (500 MHz, CD₃OD) δ 7.61 (d, J=8.4 Hz, 1H), 7.39 (d,J=1.3 Hz, 1H), 7.31-7.29 (m, 2H), 7.05-7.02 (m, 3H), 4.72 (d, J=14.9 Hz,1H), 4.62 (d, J=14.9 Hz, 1H), 3.92-3.79 (m, 2H), 3.86-3.79 (m, 5H),3.59-3.47 (m, 2H), 3.26-3.17 (m, 6H), 3.00-2.81 (m, 4H), 2.40-2.24 (m,1H), 2.24-2.00 (m, 1H), 1.38 (t, J=7.3 Hz, 3H); ESI MS m/z 449 [M+H]⁺;HPLC (Method B) 97.3% (AUC), t_(R)=10.6 min.

Example 77 Preparation of4-(Benzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)pyridin-2(1H)-onehydrochloride

a) tert-Butyl 4-(2-(6-bromopyridin-2-yl)hydrazono)azepane-1-carboxylate

tert-Butyl 4-oxoazepane-1-carboxylate (1.7 g, 8.1 mmol) was added to asolution of 2-bromo-6-hydrazinylpyridine (1.5 g, 8.1 mmol) in Et₂O (27mL), and the resulting solution was stirred at ambient temperature for1.5 h. The solution was concentrated under reduced pressure to providethe title compound (3.1 g, 99%) as a light orange solid: ¹H NMR (300MHz, DMSO-d₆) δ 9.89-9.68 (m, 1H), 7.50-7.45 (m, 1H), 7.04-7.01 (m, 1H),6.89-6.85 (m, 1H), 3.48-3.28 (m, 4H), 2.59-2.50 (m, 4H, overlaps withH₂O), 1.69-1.53 (m, 2H), 1.38-1.36 (m, 9H).

b) tert-Butyl4-(2-(6-bromopyridin-2-yl)-2-methylhydrazono)azepane-1-carboxylate

Sodium hydride (60% dispersion in oil, 0.83 g, 21 mmol) was added to asolution of tert-butyl4-(2-(6-bromopyridin-2-yl)hydrazono)azepane-1-carboxylate (6.4 g, 17mmol) in DMF (54 mL) at room temperature under N₂ and stirred for 20min. Methyl iodide (1.1 mL, 18 mmol) was added to the solution, and theresulting solution was stirred for 2 h at ambient temperature. Themixture was quenched with H₂O (100 mL). The solution was extracted withEtOAc (2×50 mL). The combined organic extracts were washed with brine(4×30 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure to afford a dark orange oil. The oil was diluted with EtOAc(100 mL) and washed with brine (6×50 mL), dried over Na₂SO₄, filteredand concentrated to dryness under reduced pressure to provide the titlecompound (7.00 g, quant.) as an amber oil: ¹H NMR (300 MHz, DMSO-d₆) δ7.44-7.36 (m, 1H), 6.88 (d, J=7.2 Hz, 1H), 6.49-6.38 (m, 1H), 3.56-3.35(m, 4H), 3.06-3.04 (m, 3H), 2.75-2.50 (m, 4H, overlaps with H₂O),1.72-1.51 (m, 2H), 1.43-1.15 (m, 9H).

c) tert-Butyl2-bromo-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate

tert-Butyl4-(2-(6-bromopyridin-2-yl)-2-methylhydrazono)azepane-1-carboxylate (6.66g, 17.3 mmol) and p-toluene sulfonic acid (6.93 g, 36.4 mmol) werestirred at 175° C. for 55 min. The mixture was cooled to ambienttemperature, and the resulting oil was diluted with 1.8:1 H₂O/iPrOH (62mL). K₂CO₃ (10.5 g, 76.1 mmol) and Boc₂O (4.15 g, 19.3 mmol) were addedto the resulting solution and the solution was stirred at ambienttemperature for 3 h. The solution was diluted with H₂O (100 mL) andextracted with EtOAc (3×75 mL). The combined organic extracts were driedover Na₂SO₄, filtered and concentrated. Flash chromatography (120 g ISCOcolumn, hexanes/EtOAc, 90:10 for 4 column volumes, increased to 50:50over 12 column volumes and held for 4 column volumes, increased to 0:100over 10 column volumes) provided the title compound (0.85 g, 12%) as ayellow powder: ¹H NMR (300 MHz, DMSO-d₆) δ 7.82 (d, J=8.1 Hz, 1H), 7.18(d, J=8.1 Hz, 1H), 3.66-3.64 (m, 5H), 3.55-3.50 (m, 2H, overlap withH₂O), 3.18-3.15 (m, 2H), 3.02-3.00 (m, 2H), 1.41 (s, 9H).

d) tert-Butyl2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate

tert-Butyl2-bromo-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate(0.27 g, 0.71 4-benzyloxy pyridinone (0.16 g, 0.78 mmol), and Cs₂CO₃(0.25 g, 0.776 mmol) were suspended in DMSO (4.2 mL), and the mixturewas degassed under vacuum for 15 min. The system was flushed with Ar,and 8-hydroxyquinoline (31 mg, 0.21 mmol) and copper iodide (0.17 g,0.92 mmol) were added to the suspension. The evacuation/Ar flushingprocess was repeated twice more, and the reaction mixture was heated at130° C. for 18 h under N₂. The mixture was cooled, diluted with5.0:3.5:1.5 NH₄Cl (aq.)/NH₄OH/H₂O (30 mL), and the resulting suspensionwas stirred at ambient temperature for 30 min. The resulting solids werecollected by filtration, dissolved in CH₂Cl₂ (30 mL) and washed with5.0:3.5:1.5 NH₄Cl (aq.)/NH₄OH/H₂O (40 mL) (2×20 mL). The resultingorganic solution was dried over Na₂SO₄, filtered and concentrated todryness under reduced pressure. Flash chromatography (12 g ISCO column,(1:1 hexanes/ EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 4 columnvolumes, increased to 50:50 over 20 column volumes and held for 4 columnvolumes) gave a crude product that was dissolved in CH₂Cl₂ (5 mL).Activated charcoal was added to the solution, and the resultingsuspension was filtered through celite. Flash chromatography (12 g ISCOcolumn, (1:1 hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0 for 4column volumes, increased to 75:25 over 20 column volumes and held for 4column volumes) followed by preparative HPLC (Phenomenex Luna C18 (2),250.0×50.0 mm, 10 micron, H₂O with 0.05% TFA and CH₃CN with 0.05% TFA)gave the title compound (0.12 g, 33%) as a clear film: ¹H NMR (500 MHz,DMSO-d₆) δ 7.94 (d, J=8.0 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.48-7.41 (m,4H), 7.38-7.37 (m, 1H), 7.25 (d, J=8.0 Hz, 1H), 6.15 (dd, J=7.5, 2.5 Hz,1H), 5.97 (d, J=2.5 Hz, 1H), 5.16 (s, 2H), 3.69-3.67 (m, 5H), 3.59-3.58(m, 2H), 3.06-3.05 (m, 2H), 2.96-2.95 (m, 2H), 1.43-1.42 (m, 9H).

e)4-(Benzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)pyridin-2(1H)-onehydrochloride

1.25 M HCl in MeOH (4 mL) was added to tert-butyl2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate(0.12 g, 0.24 mmol) and the resulting solution was stirred under N₂ atambient temperature for 18 h. The solution was concentrated to drynessto provide the title compound (0.11 g, quant.) as an orange solid: mp180-185° C. dec; ¹H NMR (500 MHz, DMSO-d₆) δ 9.19 (s, 2H), 8.02 (d,J=8.5 Hz, 1H), 7.79 (d, J=7.5 Hz, 1H), 7.48-7.41 (m, 4H), 7.38 (d, J=7.5Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 6.16 (dd, J=7.5, 2.5 Hz, 1H), 5.98 (d,J=2.5 Hz, 1H), 5.16 (s, 2H), 3.73 (s, 3H), 3.39-3.38 (m, 2H), 3.33-3.31(m, 2H), 3.30-3.28 (m, 2H), 3.14 (t, J=5.5 Hz, 2H); ESI MS m/z 401[M+H]⁺; HPLC (Method A) >99% (AUC), t_(R)=13.9 min.

Example 78 Preparation of1-(10-Methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-onehydrochloride

a) tert-Butyl10-methyl-2-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-1(2H)-yl)-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-4]azepine-7(6H)-carboxylate

tert-Butyl2-bromo-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate(0.20 g, 0.53 mmol),4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one (0.13 g, 0.55mmol), and Cs₂CO₃ (0.19 g, 0.58 mmol) were suspended in DMSO (3.0 mL),and the mixture was degassed under vacuum for 15 min. The system wasflushed with Ar, and 8-hydroxyquinoline (23 mg, 0.16 mmol) and copperiodide (0.13 g, 0.69 mmol) were added to the suspension. Theevacuation/Ar flushing process was repeated twice more, and the reactionmixture was heated at 130° C. for 18 h under N₂. The mixture was cooled,diluted with 5.0:3.5:1.5 NH₄Cl (aq.)/NH₄OH/H₂O (30 mL), and theresulting solution was stirred at ambient temperature for 6 h. Theresulting solution was diluted with CH₂Cl₂, the resulting layers wereseparated, and the aqueous phase was extracted with CH₂Cl₂ (3×25 mL).The combined organic extracts were dried over Na₂SO₄, filtered andconcentrated to dryness under reduced pressure. Flash chromatography (12g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0for 4 column volumes, increased to 50:50 over 20 column volumes and heldfor 4 column volumes, then increased to 0:100 over 20 column volumes andheld for 4 column volumes) followed by preparative HPLC (Phenomenex LunaC18 (2), 250.0×50.0 mm, 10 micron, H₂O with 0.05% TFA and CH₃CN with0.05% TFA) gave the title compound (56 mg, 19%) as a yellow solid: ¹HNMR (500 MHz, DMSO-d₆) δ 9.20 (d, J=2.0 Hz, 1H), 8.50 (dd, J=8.0, 2.0Hz, 1H), 8.06-8.03 (m, 3H), 7.36 (d, J=8.0 Hz, 1H), 7.02 (d, J=2.0 Hz,1H), 6.83 (dd, J=7.0, 2.0 Hz, 1H), 3.72-3.68 (m, 5H), 3.61-3.60 (m, 2H),3.08-3.07 (m, 2H), 2.99-2.98 (m, 2H), 1.44 (s, 9H).

b)1-(10-Methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)-4-(6-(trifluoromethyppyridin-3-yl)pyridin-2(1H)-onehydrochloride

1.25 M HCl in MeOH (3.2 mL) was added to tert-butyl10-methyl-2-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-1(2H)-yl)-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate(55 mg, 0.10 mmol), and the resulting solution was stirred under N₂ atambient temperature for 18 h. The solution was diluted with MeOH (2.2mL) and Et₂O (25 mL), and the resulting solids were collected byfiltration to provide the title compound (37 mg, 76%) as a yellowpowder: mp 320-325° C. dec; ¹H NMR (500 MHz, DMSO-d₆) δ 9.28 (s, 2H),9.21 (d, J=2.0 Hz, 1H), 8.50 (dd, J=8.5, 2.0 Hz, 1H), 8.10-8.04 (m, 3H),7.41 (d, J=8.0 Hz, 2H), 7.03 (d, J=1.5 Hz, 1H), 6.85 (dd, J=7.5, 3.5 Hz,1H), 5.98 (d, J=2.5 Hz, 1H), 3.76 (s, 3H), 3.41-3.40 (m, 2H), 3.33-3.31(m, 2H, overlaps with solvent), 3.17 (t, J=5.5 Hz, 2H); ESI MS m/z 440[M+H]⁺; HPLC (Method A) 99.0% (AUC), t_(R)=13.6 min.

Example 79 Preparation of1-(10-Methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-onehydrochloride

a) tert-Butyl10-methyl-2-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate

tert-Butyl2-bromo-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate(0.13 g, 0.35 mmol),4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one (85 mg, 0.35mmol), and Cs₂CO₃ (0.13 g, 0.39 mmol) were suspended in DMSO (2.0 mL),and the mixture was degassed under vacuum for 15 min. The system wasflushed with Ar, and 8-hydroxyquinoline (15 mg, 0.11 mmol) and copperiodide (86 mg, 0.45 mmol) were added to the suspension. Theevacuation/Ar flushing process was repeated twice more, and the reactionmixture was heated at 130° C. for 18 h under N₂. The mixture was cooled,diluted with 5.0:3.5:1.5 NH₄Cl (aq.)/NH₄OH/H₂O (30 mL), and theresulting suspension was stirred at ambient temperature for 30 min. Theresulting solids were collected by filtration, dissolved in CH₂Cl₂(30mL) and washed with 5.0:3.5:1.5 NH₄C1(aq.)/NH₄OH/H₂O (40 mL) (2×20 mL).The resulting organic solution was dried over Na₂SO₄, filtered andconcentrated to dryness under reduced pressure. Flash chromatography (12g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0for 4 column volumes, increased to 50:50 over 20 column volumes and heldfor 4 column volumes, then increased to 0:100 over 20 column volumes andheld for 4 column volumes) followed by preparative HPLC (Phenomenex LunaC18 (2), 250.0×50.0 mm, 10 micron, H₂O with 0.05% TFA and CH₃CN with0.05% TFA) gave the title compound (47 mg, 24%) as a yellow film: ¹H NMR(500 MHz, DMSO-d₆) δ 8.71 (d, J=9.0 Hz, 1H), 8.47 (d, J=8.5 Hz, 1H),8.12 (d, J=7.5 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.40-7.39 (m, 2H), 7.22(dd, J=7.0, 2.0 Hz, 1H), 3.73 (s, 3H), 3.71-3.69 (m, 2H), 3.61-3.60 (m,2H), 3.09-3.08 (m, 2H), 2.99-2.89 (m, 2H), 1.44 (s, 9H).

b) 1-(10-Methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-onehydrochloride

1.25 M HCl in MeOH (4.3 mL) was added to tert-butyl10-methyl-2-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate(47 mg, 0.087 mmol), and the resulting solution was stirred under N₂ atambient temperature for 20 h. The solution was diluted with Et₂O (25mL), and the resulting solids were collected by filtration to providethe title compound (39 mg, 94%) as a yellow solid: mp 300-305° C. dec;¹H NMR (500 MHz, DMSO-d₆) δ 9.10 (s, 2H), 8.71 (d, J=9.0 Hz, 1H), 8.47(d, J=9.0 Hz, 1H), 8.12-8.10 (m, 2H), 7.44 (d, J=8.0 Hz, 1H), 7.40 (d,J=2.0 Hz, 1H), 7.23 (dd, J=7.0, 2.0 Hz, 1H), 3.77 (s, 3H), 3.46-3.41 (m,2H), 3.38-3.34 (m, 2H), 3.32-3.30 (m, 2H, overlapped with solvent), 3.17(t, J=6.0 Hz, 2H); ESI MS m/z 441 [M+H]⁺; HPLC (Method A) >99% (AUC),t_(R)=12.8 min.

Example 80 Preparation of1-(10-Methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-onehydrochloride

a) tert-Butyl10-methyl-2-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate

tert-Butyl2-bromo-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate(0.15 g, 0.40 mmol),4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (100 mg, 0.42mmol), and Cs₂CO₃ (0.14 g, 0.43 mmol) were suspended in DMSO (2.2 mL),and the mixture was degassed under vacuum for 15 min. The system wasflushed with Ar, and 8-hydroxyquinoline (18 mg, 0.13 mmol) and copperiodide (98 mg, 0.51 mmol) were added to the suspension. Theevacuation/Ar flushing process was repeated twice more, and the reactionmixture was heated at 130° C. for 21 h under N₂. The mixture was cooled,diluted with 5.0:3.5:1.5 NH₄Cl (aq.)/NH₄OH/H₂O (30 mL), and theresulting suspension was stirred at ambient temperature for 30 min. Theresulting solids were collected by filtration, dissolved in CH₂Cl₂(30mL) and washed with 5.0:3.5:1.5 NH₄Cl (aq.)/NH₄OH/H₂O (40 mL) (2×20 mL).The resulting organic solution was dried over Na₂SO₄, filtered andconcentrated to dryness under reduced pressure. Flash chromatography (12g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0for 4 column volumes, increased to 50:50 over 20 column volumes and heldfor 4 column volumes, then increased to 0:100 over 20 column volumes andheld for 4 column volumes) followed by preparative HPLC (Phenomenex LunaC18 (2), 250.0×50.0 mm, 10 micron, H₂O with 0.05% TFA and CH₃CN with0.05% TFA) gave the title compound (32 mg, 15%) as a yellow film: ¹H NMR(500 MHz, DMSO-d₆) δ 9.15 (dd, J=1.0, 1.0 Hz, 1H), 8.39-8.34 (m, 2H),8.05-8.03 (m, 2H), 7.38 (d, J=8.5 Hz, 1H), 7.03 (d, J=2.0 Hz, 1H), 7.11(dd, J=7.0, 1.5 Hz, 1H), 3.72 (s, 3H), 3.70 (t, J=5.5 Hz, 2H), 3.61-3.58(m, 2H), 3.08-3.07 (m, 2H), 2.99-2.98 (m, 2H), 1.44-1.43 (m, 9H).

b)1-(10-Methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-onehydrochloride

1.25 M HCl in MeOH (3.0 mL) was added to tert-butyl10-methyl-2-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate(32 mg, 0.060 mmol), and the resulting solution was stirred under N₂ atambient temperature for 18 h. The solution was concentrated underreduced pressure, the resulting residue was diluted with MeOH (1 mL) andEt₂O (10 mL), and the solids were collected by filtration to provide thetitle compound (31 mg, quant.) as a yellow powder: mp 310-314° C. dec;¹H NMR (500 MHz, DMSO-d₆) δ 9.19 (s, 2H), 9.15 (dd, J=1.0, 1.0 Hz, 1H),8.41-8.35 (m, 2H), 8.09 (d, J=8.5 Hz, 1H), 8.05 (d, J=7.0 Hz, 1H), 7.43(d, J=8.5 Hz, 1H), 7.30 (d, J=2.0 Hz, 1H), 7.12 (dd, J=7.0, 2.0 Hz, 1H),3.76 (s, 3H), 3.42-3.40 (m, 2H), 3.36-3.32 (m, 2H), 3.30-3.28 (m, 2H,overlaps with H₂O), 3.17 (t, J=6.5 Hz, 2H); ESI MS m/z 440 [M+H]⁺; HPLC(Method A) 98.83% (AUC), t_(R)=13.9 min.

Example 81 Preparation of4-((5-Fluoropyridin-2-yl)methoxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)pyridin-2(1H)-onehydrochloride

a) tert-Butyl2-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate

tert-Butyl2-bromo-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate(0.15 g, 0.40 mmol), 4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one(100 mg, 0.42 mmol), and Cs₂CO₃ (0.14 g, 0.43 mmol) were suspended inDMSO (2.2 mL), and the mixture was degassed under vacuum for 15 min. Thesystem was flushed with Ar, and 8-hydroxyquinoline (18 mg, 0.13 mmol)and copper iodide (98 mg, 0.51 mmol) were added to the suspension. Theevacuation/Ar flushing process was repeated twice more, and the reactionmixture was heated at 130° C. for 21 h under N₂. The mixture was cooled,diluted with 5.0:3.5:1.5 NH₄C1(aq.)/NH₄OH/H₂O (30 mL), and the resultingsuspension was stirred at ambient temperature for 30 min. The resultingsolids were collected by filtration, dissolved in CH₂Cl₂(30 mL) andwashed with 5.0:3.5:1.5 NH₄C1(aq.)/NH₄OH/H₂O (40 mL) (2×20 mL). Theresulting organic solution was dried over Na₂SO₄, filtered andconcentrated to dryness under reduced pressure. Flash chromatography (12g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0for 4 column volumes, increased to 50:50 over 20 column volumes and heldfor 4 column volumes, then increased to 0:100 over 20 column volumes andheld for 4 column volumes) followed by preparative HPLC (Phenomenex LunaC18 (2), 250.0×50.0 mm, 10 micron, H₂O with 0.05% TFA and CH₃CN with0.05% TFA) gave the title compound (0.55 mg, 21%) as a clear film: ¹HNMR (500 MHz, DMSO-d₆) δ 8.62 (d, J=3.0 Hz, 1H), 7.97 (d, J=8.0 Hz, 1H),7.84-7.79 (m, 2H), 7.67-7.60 (m, 1H), 7.25 (d, J=8.5 Hz, 1H), 6.18 (dd,J=7.5, 2.5 Hz, 1H), 5.98 (d, J=2.5 Hz, 1H), 5.23 (s, 2H), 3.69-3.66 (m,5H), 3.62-3.57 (m, 2H), 3.08-3.04 (m, 2H), 2.99-2.94 (m, 2H), 1.43-1.42(m, 9H).

b)4((5-Fluoropyridin-2-yl)methoxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)pyridin-2(1H)-onehydrochloride

1.25 M HCl in MeOH (6.0 mL) was added to tert-butyl2-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate(0.12 g, 0.22 mmol) and the resulting solution was stirred under N₂ atambient temperature for 20 h. The resulting suspension was diluted withEt₂O (30 mL), and the resulting solids were collected by filtration toprovide the title compound (92 mg, 92%) as an off-white solid: mp238-240° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.43 (s, 2H), 8.62 (d, J=2.0Hz, 1H), 8.02 (d, J=8.5 Hz, 1H), 7.84-7.80 (m, 2H), 7.67-7.64 (m, 1H),7.30 (d, J=8.5 Hz, 1H), 6.19 (dd, J=7.5, 2.5 Hz, 1H), 5.98 (d, J=2.5 Hz,1H), 5.23 (s, 2H), 3.73 (s, 3H), 3.40-3.37 (m, 2H), 3.34-3.30 (m, 4H),3.18-3.14 (m, 2H); ESI MS m/z 420 [M+H]⁻; HPLC (Method A) 98.8% (AUC),t_(R)=13.5 min.

Example 82 Preparation of5-((5-Fluoropyridin-2-yl)methoxy)-2-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)pyridazin-3(2H)-onehydrochloride

a) tert-Butyl2-(4-((5-fluoropyridin-2-yl)methoxy)-6-oxopyridazin-1(6H)-yl)-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate

tert-Butyl2-bromo-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate(0.18 g, 0.48 mmol),5-((5-fluoropyridin-2-yl)methoxy)pyridazin-3(2H)-one (0.11 g, 0.51mmol), and Cs₂CO₃ (0.20 g, 0.63 mmol) were suspended in DMSO (2.8 mL),and the mixture was degassed under vacuum for 15 min. The system wasflushed with Ar, and 8-hydroxyquinoline (21 mg, 0.15 mmol) and copperiodide (0.23 mg, 1.2 mmol) were added to the suspension. Theevacuation/Ar flushing process was repeated twice more, and the reactionmixture was heated at 110° C. for 18 h under N₂. The mixture was cooled,diluted with 5.0:3.5:1.5 NH₄Cl (aq.)/NH₄OH/H₂O (20 mL), and theresulting solution was stirred at ambient temperature for 6 h. Theresulting solution was diluted with CH₂Cl₂, the resulting layers wereseparated, and the aqueous phase was extracted with CH₂Cl₂ (3×25 mL).Activated charcoal was added to the combined organic extracts, and theresulting suspension was filtered through a silica gel plug. Flashchromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2CH₂Cl₂/MeOH/NH₄OH), 100:0 for 2 column volumes, increased to 50:50 over10 column volumes and held for 4 column volumes, then increased to 0:100over 10 column volumes and held for 4 column volumes) gave the titlecompound (0.12 mg, 56%) as an off-white solid: ¹H NMR (500 MHz, DMSO-d₆)δ 8.63 (d, J=3.0 Hz, 1H), 8.00 (d, J=8.5 Hz, 1H), 7.96 (d, J=3.0 Hz,1H), 7.86-7.82 (m, 1H), 7.72-7.67 (m, 1H), 7.09 (d, J=8.5 Hz, 1H), 6.51(d, J=3.0 Hz, 1H), 5.30 (s, 2H), 3.69-3.67 (m, 5H), 3.60-3.57 (m, 2H),3.08-3.05 (m, 2H), 2.98-2.96 (m, 2H), 1.44-1.42 (m, 9H).

b)5-((5-Fluoropyridin-2-yl)methoxy)-2-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)pyridazin-3(2H)-onehydrochloride

1.25 M HCl in MeOH (4.0 mL) was added to tert-butyl2-(4-((5-fluoropyridin-2-yl)methoxy)-6-oxopyridazin-1(6H)-yl)-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate(55 mg, 0.11 mmol), and the resulting solution was stirred under N₂ atambient temperature for 18 h. Additional 1.25 M HCl in MeOH (2.0 mL) wasadded, and the resulting solution was stirred at ambient temperature for24 h. The resulting solution was diluted with Et₂O (30 mL), and theresulting solids were collected by filtration to provide the titlecompound (35 mg, 73%) as an off-white powder: mp 226-230° C. dec; ¹H NMR(500 MHz, DMSO-d₆) δ 9.12 (s, 2H), 8.64 (d, J=3.0 Hz, 1H), 8.06 (d,J=8.0 Hz, 1H), 7.98 (d, J=2.5 Hz, 1H), 7.85 (ddd, J=11.5, 8.5, 2.5 Hz,1H), 7.72-7.69 (m, 1H), 7.15 (d, J=8.5 Hz, 1H), 6.51 (d, J=3.0 Hz, 1H),5.30 (s, 2H), 3.71 (s, 3H), 3.45-3.39 (m, 2H), 3.38-3.31 (m, 2H),3.30-3.28 (m, 2H), 3.15-3.14 (m, 2H); ESI MS m/z 421 [M+H]⁺; HPLC(Method A) 98.8% (AUC), t_(R)=11.6 min.

Example 83 Preparation of4-(2,4-Difluorobenzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)pyridin-2(1H)-onehydrochloride

A suspension of 4-(2,4-difluorobenzyloxy)pyridin-2(1H)-one (83 mg, 0.35mmol), tert-butyl2-bromo-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate(146 mg, 0.384 mmol), CuI (80 mg, 0.42 mmol), 8-hydroxyquinoline (10 mg,0.070 mmol) and Cs₂CO₃ (125 mg, 0.384 mmol) in DMSO (10 mL) was degassedunder reduced pressure for 45 min. The suspension was put under N₂ andstirred at 135° C. for 24 h. The suspension was cooled, 9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension wasstirred at 25° C. for 30 min. The suspension was passed through a plugof silica gel, and the filtrate was washed with brine. Activated carbonwas added to the resulting solution, and the resulting suspension wasfiltered. The filtrate was dried over Na₂SO₄ and concentrated underreduced pressure. Flash chromatography on silica gel (Et₂O/(8:1.9:0.1Et₂O/MeOH/NH₄OH) afforded a cream colored solid. 2 N HCl in Et₂O (100mL) was added to a solution of the cream colored solid in CH₂Cl₂ (5 mL)under N₂, and the resulting suspension was stirred at 25° C. for 2 d.The suspension was concentrated, and the resulting residue was dissolvedin MeOH (1 mL). Et₂O (9 mL) was added, the resulting suspension wasfiltered, and the solid was washed with Et₂O and put in a vacuum oven at40° C. for 12 h to afford 40 mg (24%) of the title compound as a whitepowder: ¹H NMR (500 MHz, DMSO-d₆) δ 9.04 (br s, 2H), 8.03 (d, J=8.5 Hz,1H), 7.79 (d, J=8.0 Hz, 1H), 7.67 (dd, J=15.5, 8.5 Hz, 1H), 7.35 (ddd,J=10.0, 10.0, 2.5 Hz, 1H), 7.32 (d, J=8.5 Hz, 1H), 7.18 (ddd, J=8.5,8.5, 2.0 Hz, 1H), 6.14 (dd, J=8.0, 3.0 Hz, 1H), 6.06 (d, J=2.5 Hz, 1H),5.17 (s, 2H), 3.74 (s, 3H), 3.59-3.32 (m, 4H), 3.31-3.26 (m, 2H),3.17-3.14 (m, 2H); ESI MS m/z 437 [M+H]⁺.

Example 84 Preparation of4-(4-Chloro-2-fluorobenzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)pyridin-2(1H)-onehydrochloride

A suspension of 4-(4-chloro-2-fluorobenzyloxy)pyridin-2(1H)-one (75 mg,0.30 mmol), tert-butyl2-bromo-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate(91 mg, 0.33 mmol), CuI (67 mg, 0.36 mmol), 8-hydroxyquinoline (9 mg,0.06 mmol) and Cs₂CO₃ (106 mg, 0.326 mmol) in DMSO (10 mL) was degassedunder reduced pressure for 45 min. The suspension was put under N₂ andstirred at 135° C. for 24 h. The suspension was cooled, 9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension wasstirred at 25° C. for 30 min. The suspension was passed through a plugof silica gel, and the filtrate was washed with brine. Activated carbonwas added to the resulting solution, and the resulting suspension wasfiltered. The filtrate was dried over Na₂SO₄, and concentrated underreduced pressure. Flash chromatography on silica gel (Et₂O/(8:1.9:0.1Et₂O/MeOH/NH₄OH) afforded a cream colored solid. 2 N HCl in Et₂O (100mL) was added to a solution of the cream colored solid in CH₂Cl₂ (5 mL)under N₂, and the resulting suspension was stirred at 25° C. for 2 d.The suspension was concentrated, and the resulting residue was dissolvedin MeOH (1 mL). Et₂O (4 mL) was added, and the resulting suspension wasfiltered, the solid was washed with Et₂O and the solid was put in avacuum oven at 40° C. for 2 d to afford 20 mg (14%) of the titlecompound as a white powder: ¹H NMR (500 MHz, DMSO-d₆) δ 9.00 (br s, 2H),8.03 (d, J=8.5 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.64 (dd, J=8.0, 8.0 Hz,1H), 7.54 (dd, J=10.0, 1.5 Hz, 1H), 7.39 (br d, J=8.5 Hz, 1H), 7.32 (d,J=8.0 Hz, 1H), 6.15 (dd, J=8.0, 3.0 Hz, 1H), 6.05 (d, J=2.5 Hz, 1H),5.19 (s, 2H), 3.74 (s, 3H), 3.60-3.32 (m, 4H), 3.31-3.26 (m, 2H),3.17-3.12 (m, 2H); ESI MS m/z 453 [M+H]⁺.

Example 85 Preparation of4-((5-Chloropyridin-2-yl)methoxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)pyridin-2(1H)-onehydrochloride

A suspension of 4-((5-chloropyridin-2-yl)methoxy)pyridin-2(1H)-one (67mg, 0.28 mmol), tert-butyl2-bromo-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate(129 mg, 0.339 mmol), CuI (64 mg, 0.34 mmol), 8-hydroxyquinoline (8 mg,0.06 mmol) and Cs₂CO₃ (101 mg, 0.311 mmol) in DMSO (10 mL) was degassedunder reduced pressure for 45 min. The suspension was put under N₂, andstirred at 135° C. for 16 h. The suspension was cooled, 9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension wasstirred at 25° C. for 30 min. The suspension was passed through a plugof silica gel, and the filtrate was washed with brine. Activated carbonwas added to the resulting solution, and the resulting suspension wasfiltered. The filtrate was dried over Na₂SO₄ and concentrated underreduced pressure afforded a tan solid. 2 N HCl in Et₂O (100 mL) wasadded to a solution of the tan solid in CH₂Cl₂ (5 mL) under N₂, and theresulting suspension was stirred at 25° C. for 15 h. The suspension wasfiltered, and the solid was washed with Et₂O and freeze dried to afford51 mg (36%) of the title compound as an off-white powder: ¹H NMR (500MHz, DMSO-d₆) δ 9.17 (br s, 2H), 8.68 (s, 1H), 8.07-8.00 (m, 2H), 7.81(d, J=8.0 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 6.20(br d, J=6.0 Hz, 1H), 5.97 (br s, 1H), 5.25 (s, 2H), 3.73 (s, 3H),3.44-3.21 (m, 6H), 3.19-3.11 (m, 2H); ESI MS m/z 436 [M+H]⁺.

Example 86 Preparation of4-(Benzyloxy)-1-(7-cyclobutyl-10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)pyridin-2(1H)-onehydrochloride

2-Picoline borane (43 mg, 0.40 mmol) was added to a solution of4-(benzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)pyridin-2(1H)-onehydrochloride (58 mg, 0.13 mmol) and cyclobutanone (0.10 mL, 1.3 mmol)in 9:1 CH₂Cl₂/AcOH (10 mL), and the resulting solution was stirred at25° C. for 15 h. Saturated NaHCO₃ solution was added to the reactionsolution, and the phases were separated. The organic phase was driedover Na₂SO₄ and concentrated under reduced pressure. Flashchromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded a white solid. 2 N HCl inEt₂O (0.05 mL, 0.1 mmol) was added to a solution of the white solid inCH₂Cl₂ (5 mL) under N₂, and the resulting solution was stirred at 25° C.for 30 min. The solution was concentrated under reduced pressure andfreeze dried to afford 40 mg (63%) of the title compound as a whitepowder: ¹H NMR (500 MHz, DMSO-d₆) δ 10.65 (br s, 1H), 8.04 (d, J=8.0 Hz,1H), 7.80 (d, J=8.0 Hz, 1H), 7.50-7.35 (m, 5H), 7.33 (d, J=8.5 Hz, 1H),6.17 (dd, J=7.5, 2.0 Hz, 1H), 5.99 (d, J=2.0 Hz, 1H), 5.17 (s, 2H),3.99-3.88 (m, 1H), 3.73 (s, 3H), 3.61-3.52 (m, 2H), 3.41-3.17 (m, 4H),3.15-3.07 (m, 2H), 2.41-2.25 (m, 4H), 1.83-1.60 (m, 2H); ESI MS m/z 455[M+H]⁺.

Example 87 Preparation of4-(Benzyloxy)-1-(7-ethyl-10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)pyridin-2(1H)-onehydrochloride

2-Picoline borane (45 mg, 0.42 mmol) was added to a solution of4-(benzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)pyridin-2(1H)-onehydrochloride (62 mg, 0.14 mmol) and acetaldehyde (0.08 mL, 1.4 mmol) in9:1 CH₂Cl₂/AcOH (10 mL), and the resulting solution was stirred at 25°C. for 2 h. Saturated NaHCO₃ solution was added to the reactionsolution, and the phases were separated. The organic phase was driedover Na₂SO₄ and concentrated under reduced pressure. Flashchromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded a white solid. 2 N HCl inEt₂O (0.05 mL, 0.1 mmol) was added to a solution of the white solid inCH₂Cl₂ (5 mL) under N₂, and the resulting solution was stirred at 25° C.for 30 min. The solution was concentrated under reduced pressure andfreeze dried to afford 48 mg (76%) of the title compound as an off-whitepowder: ¹H NMR (500 MHz, DMSO-d₆) δ 10.26 (br s, 1H), 8.04 (d, J=8.5 Hz,1H), 7.79 (d, J=7.5 Hz, 1H), 7.50-7.36 (m, 5H), 7.32 (d, J=8.0 Hz, 1H),6.17 (dd, J=7.5, 2.5 Hz, 1H), 5.99 (d, J=2.5 Hz, 1H), 5.17 (s, 2H),3.77-3.62 (m, 5H), (m, 8H), 1.32 (t, J=7.0 Hz, 3H); ESI MS m/z 429[M+H]⁺.

Example 88 Preparation of4-(Benzyloxy)-1-(7,10-dimethyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)pyridin-2(1H)-onehydrochloride

2-Picoline borane (48 mg, 0.45 mmol) was added to a solution of4-(benzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)pyridin-2(1H)-onehydrochloride (66 mg, 0.15 mmol) and formaldehyde (37% weight solutionin H₂O, 0.06 mL, 0.8 mmol) in 9:1 CH₂Cl₂/AcOH (10 mL), and the resultingsolution was stirred at 25° C. for 1 h. Saturated NaHCO₃ solution wasadded to the reaction solution, and the phases were separated. Theorganic phase was dried over Na₂SO₄ and concentrated under reducedpressure. Flash chromatography (silica gel, (1:1EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded awhite solid. 2 N HCl in Et₂O (0.04 mL, 0.08 mmol) was added to asolution of the white solid in CH₂Cl₂ (5 mL) under N₂, and the resultingsolution was stirred at 25° C. for 30 min. The solution was concentratedunder reduced pressure and freeze dried to afford 21 mg (31%) of thetitle compound as a white powder: ¹H NMR (500 MHz, DMSO-d₆) δ10.35-10.20 (m, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H),7.50-7.35 (m, 5H), 7.32 (d, J=8.0 Hz, 1H), 6.17 (dd, J=7.5, 2.5 Hz, 1H),5.99 (d, J=2.5 Hz, 1H), 5.17 (s, 2H), 3.74 (s, 3H), 3.73-3.63 (m, 2H),3.43-3.22 (m, 5H), 3.12-3.03 (m, 1H), 2.97 (br s, 3H); ESI MS m/z 415[M+H]⁺.

Example 89 Preparation of1-(10-Methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepin-2-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-onehydrochloride

a) tert-Butyl10-methyl-2-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-1(2H)-yl)-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate

tert-butyl2-bromo-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate(0.15 g, 0.40 mmol),4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one (95 mg, 0.40 mmol),and Cs₂CO₃ (0.14 g, 0.44 mmol) were suspended in DMSO (2.3 mL), and themixture was degassed under vacuum for 15 min. The system was flushedwith Ar, and 8-hydroxyquinoline (17 mg, 0.12 mmol) and copper iodide (91mg, 0.48 mmol) were added to the suspension. The evacuation/Ar flushingprocess was repeated twice more, and the reaction mixture was heated at130° C. for 18 h under N₂. The mixture was cooled, diluted with5.0:3.5:1.5 NH₄Cl (aq.)/NH₄OH/H₂O (30 mL), and the resulting suspensionwas stirred at ambient temperature for 30 min. The resulting solids werecollected by filtration, dissolved in CH₂Cl₂ (40 mL) and washed with5.0:3.5:1.5 NH₄C1(aq.)/NH₄OH/H₂O (2×30 mL). The resulting organicsolution was dried over Na₂SO₄ and filtered. Activated charcoal wasadded to the filtrate, the resulting suspension was filtered through acelite plug with 80:18:2 CH₂Cl₂/MeOH/NH₄OH, and the filtrate wasconcentrated to dryness under reduced pressure. Flash chromatography (12g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH₂Cl₂/MeOH/NH₄OH), 100:0for 4 column volumes, increased to 50:50 over 20 column volumes and heldfor 4 column volumes; increased to 0:100 over 10 column volumes) gavethe title compound (149 mg, 70%) as a yellow film:

¹H NMR (500 MHz, DMSO-d₆) δ 9.20 (d, J=2.0 Hz, 1H), 8.50 (dd, J=8.0, 1.5Hz, 1H), 8.07-8.02 (m, 3H), 7.39 (d, J=8.5 Hz, 1H), 7.02 (d, J=2.0 Hz,1H), 6.84 (dd, 7.5, 2.0 Hz, 1H), 4.61 (s, 2H), 3.74 (s, 3H), 3.68 (t,J=5.5 Hz, 2H), 3.05 (t, J=5.5 Hz, 2H), 1.98-1.93 (m, 2H), 1.36-1.28 (m,9H).

b)1-(10-Methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepin-2-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-onehydrochloride

A suspension of tert-butyl10-methyl-2-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-1(2H)-yl)-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-d]azepine-6(5H)-carboxylate(149 mg, 0.276 mmol) in 1.25 M HCl in MeOH (3.0 mL) was stirred under N₂at ambient temperature for 18 h. CH₂Cl₂ (1.5 mL) was added to thesuspension and the resulting solution was stirred at ambient temperaturefor 18 h. CH₂Cl₂ (1.0 mL) and 1.25 M HCl in MeOH (1.0 mL) were added tothe solution, and the resulting solution was stirred at ambienttemperature for 6 h. Additional 1.25 M HCl in MeOH (2.0 mL) was added tothe solution, and the resulting solution was stirred for 18 h. Thesolution was diluted with Et₂O, and the resulting solids were collectedby filtration to afford the title compound (104 mg, 79%) as alight-yellow powder: mp 308-312° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 9.21(d, J=2.0 Hz, 1H), 9.04 (s, 2H), 8.50 (dd, J=8.0, 2.0 Hz, 1H), 8.22 (d,J=8.0 Hz, 1H), 8.09-8.05 (m, 2H), 7.47 (d, J=8.0 Hz, 1H), 7.03 (d, J=2.0Hz, 1H), 6.85 (dd, J=7.5, 2.0 Hz, 1H), 4.49 (s, 2H), 3.80 (s, 3H),3.49-3.46 (m, 2H), 3.17-3.15 (m, 2H), 2.09-2.07 (m, 2H); ESI MS m/z 440[M+H]⁺; HPLC (Method A) 98.1% (AUC), t_(R)=13.4 min.

Example 90 Preparation of4-(Benzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepin-2-yl)pyridin-2(1H)-onehydrochloride

a) 2-Bromo-6-hydrazinylpyridine (CAS Registry Number 26944-71-8)(Yakhontov et al., Khimiya Geterotsiklicheskikh Soedinenii 6:1121-1126(1969), which is hereby incorporated by reference in its entirety)

Hydrazine (27 mL, 83 mmol) was added to 2,6-dibromopyridine (20 g, 84mmol), and the resulting suspension was heated at 70° C. for 30 min. Thesolution was cooled to 50° C. and diluted with H₂O (150 mL). Theresulting solids were stirred for 2 h. The solids were collected byfiltration and washed with H₂O (350 mL) to afford the title compound (13g, 83%) as a white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 7.87 (s, 1H), 7.34(t, J=7.8 Hz, 1H), 6.66 (t, J=7.8 Hz, 2H), 4.19 (s, 2H).

b) 2-Bromo-6-(2-cyclohexylidenehydrazinyl)pyridine (CAS Registry Number20798-52-1) (Yakhontov et al., Zhurnal Organicheskoi Khimii 4:1675-1678(1968), which is hereby incorporated by reference in its entirety)

Cyclohexanone (2.8 mL, 27 mmol) was added to a solution of2-bromo-6-hydrazinylpyridine (5.1 g, 27 mmol) in Et₂O (92 mL), and theresulting solution was stirred at ambient temperature for 1 h. Thesolution was concentrated under reduced pressure to provide the titlecompound (7.3 g, quant.) as an off-white foam: ¹H NMR (500 MHz, DMSO-d₆)δ 9.86 (s, 1H), 7.46 (dd, J=8.0, 8.0 Hz, 1H), 7.01 (d, J=8.0 Hz, 1H),6.83 (dd, J=7.5, 0.5 Hz, 1H), 2.45 (s, 2H), 2.25 (t, J=6.0 Hz, 2H),1.62-1.61 (m, 2H), 1.56-1.55 (m, 4H).

c) 2-Bromo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b] indole (CAS RegistryNumber 20798-17-8) (Yakhontov et al., Zhurnal Organicheskoi Khimii4:1675-1678 (1968), which is hereby incorporated by reference in itsentirety)

Following a procedure similar to that of Yakhontov and Pronina (ZhurnalOrganicheskoi Khimii 1968, 4, 1675-1678),2-bromo-6-(2-cyclohexylidenehydrazinyl)pyridine (9.9 g, 37 mmol) andp-toluene sulfonic acid (15 g, 77 mmol) were heated at 160° C. for 25min. The resulting solution was cooled to ambient temperature anddiluted with H₂O (100 mL) and saturated NaHCO₃ solution (50 mL). EtOAc(100 mL) was added, and the resulting solids were collected byfiltration. The filtrate was extracted with EtOAc (3×50 mL), and thecombined organic extracts were dried over Na₂SO₄, filtered andconcentrated to dryness under reduced pressure. The residue was stirredin EtOAc (50 mL), and the resulting solids were removed by filtration toprovide additional crude title compound. The solids were combined andwashed with 5:1 MeOH/CH₂Cl₂ and EtOAc sequentially to provide the titlecompound (3.4 g, 37%) as a tan solid: ¹H NMR (500 MHz, DMSO-d₆) δ 11.42(s, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 2.68 (t, J=6.0Hz, 2H), 2.59 (t, J=6.0 Hz, 2H), 1.84-1.76 (m, 4H).

d) 2-Bromo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-5-one

A solution of 2-bromo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole (3.84 g,15.2 mmol) in THF (135 mL) and H₂O (15.2 mL) was cooled to 0° C. andtreated with a solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone(6.92 g, 30.5 mmol) in THF (60.3 mL) at such a rate that the reactionmixture did not exceed 0° C. The resulting solution was warmed toambient temperature and stirred for 5 h. The solution was diluted withsaturated NaHCO₃ solution (100 mL), and the aqueous solution wasextracted with EtOAc (3×75 mL). The combined organic extracts were driedover Na₂SO₄, filtered and concentrated to dryness under reducedpressure. Flash chromatography (80 g ISCO dry load 80:18:2CH₂Cl₂/MeOH/NH₄OH, 1000 mL) followed by trituration with MeOH providedthe title compound (1.58 g, 39%) as an off-white solid: ¹H NMR (500 MHz,THF-d₈) δ 8.23 (d, J=8.0 Hz, 1H), 7.32 (d, J=8.0, 1H), 4.73 (s, 1H),3.02 (t, J=8.0 Hz, 2H), 2.51-2.47 (m, 2H), 2.27-2.22 (m, 2H); ESI MS m/z265 [M+H]⁺.

e) 2-Bromo-9-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-5-one

Methyl iodide (0.45 mL, 7.1 mmol) was added to a solution of2-bromo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-5-one (1.6 g, 5.9 mmol)and Cs₂CO₃ (2.3 g, mmol) in DMF (21 mL) under N₂ and stirred for 3 h atambient temperature. The mixture was quenched with H₂O (30 mL), uponwhich a solid precipitated out of solution. The solids were collected byfiltration and washed with H₂O (100 mL) to provide the title compound(1.47 g, 88%) as an off-white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 8.18(d, J=8.1 Hz, 1H), 7.43 (d, J=7.8 Hz, 1H), 3.74 (s, 3H), 3.03 (t, J=6.0Hz, 2H), 2.50-2.44 (m, 2H, overlap with H₂O peak), 2.20-2.12 (m, 2H).

f) 2-Bromo-9-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-5-one oxime

Hydroxylamine hydrochloride (0.54 g, 7.9 mmol) and sodium acetate (0.65g, 7.9 mmol) were added to a suspension of2-bromo-9-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-5-one (1.5 g,5.3 mmol) in EtOH (13 mL) and H₂O (5 mL), and the resulting suspensionwas heated at reflux for 4 h. The reaction was cooled to ambienttemperature, and the solids were collected by filtration. The solidswere washed with EtOH to provide the title compound (1.34 g, 87%) as anoff-white powder: ¹H NMR (500 MHz, DMSO-d₆) δ 10.49 (s, 1H), 8.05 (d,J=8.0 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 3.68 (s, 3H), 2.86 (t, J=6.0 Hz,2H), 2.68 (t, J=8.0 Hz, 2H), 1.96-1.84 (m, 2H).

g)2-Bromo-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepin-5(6H)-one

A suspension of2-bromo-9-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-5-one oxime(1.3 g, 4.5 mmol) in PPA (20 g) was mechanically rotated in a water bathset at 100° C. for 8 h. The reaction mixture was cooled in an ice bathand quenched with H₂O. 6 N NaOH solution was added until ˜pH 7 andsolids precipitated out of solution. The solids were collected byfiltration and washed with H₂O to provide the title compound (1.2 g,89%) as an off-white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 8.43 (d, J=8.0Hz, 1H), 7.69 (t, J=5.0 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H) 3.69 (s, 3H),3.23-3.20 (m, 2H), 3.12 (t, J=6.5 Hz, 2H), 2.07-2.05 (m, 2H).

h) tert-Butyl2-bromo-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate

BH₃.THF (1.0 M solution in THF, 23 mL, 23 mmol) was slowly added to asolution of2-bromo-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepin-5(6H)-one(0.50 g, 1.7 mmol) in THF (28 mL), and the resulting solution was heatedat reflux for 18 h. The reaction was cooled, and 12 N HCl (˜6 mL) wasadded slowly. The solution was diluted with H₂O (60 mL) and heated atreflux for 4 h. The solution was cooled to ambient temperature and madebasic by the slow addition of aqueous 6 N NaOH. The solution wasextracted with EtOAc (100 mL) and CH₂Cl₂ (2×50 mL). The combined organicextracts were dried over Na₂SO₄, filtered and concentrated under reducedpressure to provide a yellow film. DMAP (23 mg, catalytic) and Boc₂O(0.48 g, 2.2 mmol) were added to a solution of the yellow film in CH₂Cl₂(7 mL) under N₂, and the resulting solution was stirred at ambienttemperature for 18 h. The solution was diluted with H₂O and extractedwith CH₂Cl₂ (3×25 mL). The combined organic extracts were washed withbrine (20 mL), dried over Na₂SO₄, filtered, and concentrated to drynessunder reduced pressure. Flash chromatography (40 g ISCO column,hexanes/EtOAc, 90:10 for 4 column volumes, increased to 50:50 over 12column volumes and held for 2 column volumes; increased to 0:100 over 10column volumes) provided the title compound (0.52 g, 81%) as a whitesolid: ¹H NMR (500 MHz, DMSO-d₆) δ 7.82 (d, J=7.5 Hz, 1H), 7.22 (d,J=7.5 Hz, 1H), 4.55-4.51 (m, 2H), 3.68 (s, 3H), 3.64 (t, J=5.0 Hz, 2H),2.98 (t, J=5.5 Hz, 2H), 1.94-1.90 (m, 2H), 1.35-1.22 (m, 9H).

i) tert-Butyl2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate

A suspension of tert-butyl2-bromo-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate(0.15 g, 0.40 mmol), 4-benzyloxypyridinone (80 mg, 0.40 mmol), andCs₂CO₃ (0.14 g, 0.44 mmol) in DMSO (2.3 mL) was placed under vacuum for15 min. The system was flushed with Ar, and 8-hydroxyquinoline (17 mg,0.12 mmol) and copper iodide (91 mg, 0.48 mmol) were added to thesuspension. The evacuation/Ar flushing process was repeated twice more,and the reaction mixture was heated at 130° C. for 18 h under N₂. Themixture was cooled, diluted with 5.0:3.5:1.5 NH₄Cl (aq.)/NH₄OH/H₂O (30mL), and the resulting suspension was stirred at ambient temperature for30 min. The resulting solids were collected by filtration, dissolved inCH₂Cl₂ (40 mL) and washed with 5.0:3.5:1.5 NH₄Cl (aq.)/NH₄OH/H₂O (2×30mL). The resulting organic solution was dried over Na₂SO₄, filtered, andconcentrated to dryness under reduced pressure. Flash chromatography (12g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2

CH₂Cl₂/MeOH/NH₄OH), 100:0 for 4 column volumes, increased to 50:50 over20 column volumes and held for 4 column volumes; increased to 0:100 over10 column volumes) gave the title compound (141 mg, 70%) as an off-whitesolid: ¹H NMR (300 MHz, DMSO-d₆) δ 7.98-7.95 (m, 1H), 7.81-7.79 (m, 1H),7.49-7.37 (m, 5H), 7.30-7.27 (m, 1H), 6.15 (dd, J=7.8, 2.7 Hz, 1H), 5.98(d, J=2.7 Hz, 1H), 5.16 (s, 2H), 4.58 (br s, 2H), 3.71 (s, 3H), 3.66 (t,J=5.4 Hz, 2H), 3.03-3.01 (m, 2H), 1.98-1.93 (m, 2H), 1.35-1.27 (m, 9H);ESI MS m/z 501 [M+H]⁺.

j)4-(Benzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepin-2-yl)pyridin-2(1H)-onehydrochloride

A solution of tert-butyl2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate(140 mg, 0.028 mmol) in 1.25 M HCl in MeOH (6.0 mL) was stirred under N₂at ambient temperature for 18 h. Additional 1.25 M HCl in MeOH wasadded, and the solution was stirred at ambient temperature for 18 h. Thesolution was concentrated to dryness to yield the title compound (130mg, quant.) as a light-yellow powder: mp 328-332° C.; ¹H NMR (500 MHz,DMSO-d₆) δ 9.20 (s, 2H), 8.16 (d, J=8.0 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H),7.48-7.41 (m, 4H), 7.38-7.34 (m, 2H), 6.17 (dd, J=7.5, 2.5 Hz, 1H), 5.98(d, J=2.5 Hz, 1H), 5.17 (s, 2H), 4.46 (s, 2H), 3.75 (s, 3H), 3.44-3.43(m, 2H), 3.14-3.12 (m, 2H), 2.09-2.07 (m, 2H); ESI MS m/z 401 [M+H]⁺;HPLC (Method A) >99% (AUC), t_(R)=13.3 min.

Example 91 Preparation of4-((5-Fluoropyridin-2-yl)methoxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepin-2-yl)pyridin-2(1H)-onehydrochloride

a) tert-Butyl2-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate

tert-Butyl2-bromo-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate(0.21 g, 0.56 mmol), 4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one(0.12 g, 0.56 mmol), and Cs₂CO₃ (0.12 g, 0.61 mmol) were suspended inDMSO (3.2 mL), and the mixture was degassed under vacuum for 15 min. Thesystem was flushed with Ar, and 8-hydroxyquinoline (24 mg, 0.17 mmol)and copper iodide (0.13 g, 0.67 mmol) were added to the suspension. Theevacuation/Ar flushing process was repeated twice more, and the reactionmixture was heated at 130° C. for 18 h under N₂. The mixture was cooled,diluted with 5.0:3.5:1.5 NH₄Cl (aq.)/NH₄OH/H₂O (30 mL), and theresulting suspension was stirred at ambient temperature for 30 min. Theresulting solids were collected by filtration, dissolved in CH₂Cl₂ (40mL) and washed with 5.0:3.5:1.5 NH₄C1(aq.)/NH₄OH/H₂O (2×30 mL). Theresulting organic solution was dried over Na₂SO₄ and filtered. Activatedcharcoal was added to the filtrate; the resulting suspension wasfiltered through a celite plug with 80:18:2 CH₂Cl₂/MeOH/NH₄OH; and thefiltrate was concentrated to dryness under reduced pressure. Flashchromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2CH₂Cl₂/MeOH/NH₄OH), 100:0 for 4 column volumes, increased to 50:50 over20 column volumes and held for 4 column volumes; increased to 0:100 over10 column volumes) gave the title compound (130 mg, 45%) as an off-whitefoam: ¹H NMR (500 MHz, DMSO-d₆) δ 8.62 (d, J=3.0 Hz, 1H), 7.97 (dd,J=7.5, 7.5 Hz, 1H), 7.84-7.80 (m, 2H), 7.67-7.64 (m, 1H), 7.28 (dd,J=8.5, 8.5 Hz, 1H), 6.17 (dd, J=7.5, 2.5 Hz, 1H), 5.98 (d, J=2.5 Hz,1H), 5.23 (s, 2H), 4.58 (s, 2H), 3.71 (s, 3H), 3.66 (t, J=5.0 Hz, 2H),3.03 (t, J=6.0 Hz, 2H), 1.94-1.91 (m, 2H), 1.35-1.27 (m, 9H).

b)4-((5-Fluoropyridin-2-yl)methoxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepin-2-yl)pyridin-2(1H)-onehydrochloride

A suspension of tert-butyl2-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate(130 mg, 0.250 mmol) in 1.25 M HCl in MeOH (4.0 mL) was stirred atambient temperature for 72 h. The solution was concentrated and dried toprovide the title compound (108 mg, 95%) as a brown-yellow powder: ¹HNMR (500 MHz, DMSO-d₆) δ 9.15 (s, 2H), 8.62 (d, J=3.0 Hz, 1H), 8.16 (d,J=8.5 Hz, 1H), 7.88-7.80 (m, 2H), 7.67-7.64 (m, 1H), 7.35 (d, J=8.0 Hz,1H), 6.19 (dd, J=8.0, 2.5 Hz, 1H), 5.99 (d, J=2.5 Hz, 1H), 5.23 (s, 2H),4.46 (s, 2H), 3.75 (s, 3H), 3.49-3.40 (m, 2H), 3.36-3.20 (m, 2H),2.19-2.08 (m, 2H); ESI MS m/z 420 [M+H]⁺; HPLC (Method A) 98.2% (AUC),t_(R)=12.2 min.

Example 92 Preparation of1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepin-2-yl)-4-(5-(trifluoromethyl)pyridine-2-yl)pyridin-2(1H)-onehydrochloride

A suspension of 4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-2(1H)-one (72mg, 0.30 mmol), tert-butyl2-bromo-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate(125 mg, 0.329 mmol), CuI (64 mg, 0.34 mmol), 8-hydroxyquinoline (9 mg,0.06 mmol) and Cs₂CO₃ (107 mg, 0.329 mmol) in DMSO (10 mL) was degassedunder reduced pressure for 45 min. The suspension was put under N₂ andstirred at 135° C. for 24 h. The suspension was cooled, 9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension wasstirred at 25° C. for 20 min. The suspension was passed through a plugof silica gel, and the filtrate was washed with brine. Activated carbonwas added to the resulting solution, and the resulting suspension wasfiltered. The filtrate was dried over Na₂SO₄ and concentrated underreduced pressure. Flash chromatography on silica gel ((1:1EtOAc/hexanes)/(9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH), 100:0 to 0:100) afforded ayellow foam. 1.25 N HCl in MeOH (5 mL) was added to the yellow foamunder N₂, and the resulting suspension was stirred at 25° C. for 20 h.The suspension was concentrated; the residue was diluted with MeOH (5mL); and the suspension was sonicated for 5 min. Et₂O (50 mL) was added,and the suspension was filtered to afford 33 mg (23%) of the titlecompound as a yellow solid: ¹H NMR (500 MHz, DMSO-d₆) δ 9.20 (s, 1H),8.89 (br s, 2H), 8.43-8.35 (m, 2H), 8.23 (d, J=8.5 Hz, 1H), 8.07 (d,J=8.5 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.31 (d, J=1.5, 1H), 7.13 (dd,J=8.0, 2.0 Hz, 1H), 4.53-4.48 (m, 2H), 3.80 (s, 3H), 3.51-3.45 (m, 2H),3.19-3.15 (m, 2H), 2.12-2.08 (m, 2H); ESI MS m/z 440 [M+H]⁺.

Example 93 Preparation of4-(2,4-Dichlorobenzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepin-2-yl)pyridin-2(1H)-onehydrochloride

A suspension of 4-(2,4-dichlorobenzyloxy)pyridin-2(1H)-one (85 mg, 0.31mmol), tert-butyl2-bromo-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate(131 mg, 0.345 mmol), CuI (71 mg, 0.38 mmol), 8-hydroxyquinoline (9 mg,0.06 mmol) and Cs₂CO₃ (112 mg, 0.345 mmol) in DMSO (10 mL) was degassedunder reduced pressure for 45 min. The suspension was put under N₂ andstirred at 135° C. for 18 h. The suspension was cooled, 9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension wasstirred at 25° C. for 30 min. The suspension was passed through a plugof silica gel, and the filtrate was washed with brine. Activated carbonwas added to the resulting solution, and the resulting suspension wasfiltered. The filtrate was dried over Na₂SO₄ and concentrated underreduced pressure. Flash chromatography on silica gel (Et₂O/(8:1.9:0.1Et₂O/MeOH/NH₄OH), 100:0 to 0:100) afforded a tan solid. 2 N HCl in Et₂O(100 mL) was added to a solution of the tan solid in CH₂Cl₂ (5 mL) underN₂, and the resulting suspension was stirred at 25° C. for 24 h. Thesuspension was filtered, and the solid was washed with Et₂O and put in avacuum oven at 45° C. for 1 h to afford 102 mg (64%) of the titlecompound as a white powder: ¹H NMR (500 MHz, DMSO-d₆) δ 8.88-8.81 (m,2H), 8.16 (d, J=8.5 Hz, 1H), 7.83 (d, J=7.5 Hz, 1H), 7.74 (d, J=2.5 Hz,1H), 7.67 (d, J=7.5 Hz, 1H), 7.53 (dd, J=8.0, 2.0 Hz, 1H), 7.38 (d,J=8.0 Hz, 1H), 7.18 (dd, J=8.0, 2.5 Hz, 1H), 6.03 (d, J=2.5 Hz, 1H),5.21 (s, 2H), 4.52-4.48 (m, 2H), 3.77 (s, 3H), 3.50-3.43 (m, 2H),3.19-3.12 (m, 2H), 2.13-2.05 (m, 2H); ESI MS m/z 469 [M+H]⁻

Example 94 Preparation of4-(2,4-Difluorobenzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepin-2-yl)pyridin-2(1H)-onehydrochloride

A suspension of 4-(2,4-difluorobenzyloxy)pyridin-2(1H)-one (68 mg, 0.29mmol), tert-butyl2-bromo-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate(120 mg, 0.316 mmol), CuI (65 mg, 0.34 mmol), 8-hydroxyquinoline (8 mg,0.06 mmol) and Cs₂CO₃ (103 mg, 0.316 mmol) in DMSO (10 mL) was degassedunder reduced pressure for 45 min. The suspension was put under N₂ andstirred at 135° C. for 24 h. The suspension was cooled, 9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension wasstirred at 25° C. for 30 min. The suspension was passed through a plugof silica gel, and the filtrate was washed with brine. Activated carbonwas added to the resulting solution, and the resulting suspension wasfiltered. The filtrate was dried over Na₂SO₄ and concentrated underreduced pressure. Flash chromatography on silica gel (Et₂O/(8:1.9:0.1Et₂O/MeOH/NH₄OH) afforded a tan residue. 2 N HCl in Et₂O (100 mL) wasadded to a solution of the tan residue in CH₂Cl₂ (5 mL) under N₂, andthe resulting suspension was stirred at 25° C. for 2 d. The suspensionwas filtered, and the solid was washed with Et₂O and put in a vacuumoven at 40° C. for 1 h to afford 47 mg (35%) of the title compound as awhite powder: ¹H NMR (500 MHz, DMSO-d₆) δ 8.86 (br s, 2H), 8.16 (d,J=8.5 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.67 (dd, J=15.5, 8.5 Hz, 1H),7.40-7.34 (m, 2H), 7.18 (ddd, J=8.5, 8.5, 2.5 Hz, 1H), 7.15 (dd, J=8.0,3.0 Hz, 1H), 6.06 (d, J=2.5 Hz, 1H), 5.17 (s, 2H), 4.51-4.45 (m, 2H),3.77 (s, 3H), 3.60-3.42 (m, 2H), 3.17-3.13 (m, 2H), 2.12-2.05 (m, 2H);ESI MS m/z 437 [M+H]⁺.

Example 95 Preparation of1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepin-2-yl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-onehydrochloride

A suspension of 4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one (79 mg,0.33 mmol), tert-butyl2-bromo-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate(114 mg, 0.300 mmol), CuI (68 mg, 0.36 mmol), 8-hydroxyquinoline (9 mg,0.06 mmol) and Cs₂CO₃ (108 mg, 0.33 mmol) in DMSO (10 mL) was degassedunder reduced pressure for 45 min. The suspension was put under N₂ andstirred at 135° C. for 18 h. The suspension was cooled, 9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension wasstirred at 25° C. for 30 min. The suspension was passed through a plugof silica gel, and the filtrate was washed with brine. Activated carbonwas added to the resulting solution, and the resulting suspension wasfiltered. The filtrate was dried over Na₂SO₄ and concentrated underreduced pressure. Flash chromatography on silica gel (Et₂O/(8:1.9:0.1Et₂O/MeOH/NH₄OH) afforded a yellow solid. Preparative HPLC (PhenomenexLuna C18 (2), 250.0×50.0 mm, 10 micron, H₂O with 0.05% TFA and CH₃CNwith 0.05% TFA) afforded a yellow residue. 2 N HCl in Et₂O (100 mL) wasadded to a solution of the yellow residue in CH₂Cl₂ (5 mL) under N₂, andthe resulting suspension was stirred at 25° C. for 18 h. The suspensionwas filtered, and the solid was washed with Et₂O and put in a vacuumoven at 50° C. for 1.5 h to afford 45 mg (34%) of the title compound asa white powder: ¹H NMR (500 MHz, DMSO-d₆) δ 8.91 (br s, 2H), 8.22 (d,J=8.0 Hz, 1H), 8.05-8.00 (m, 3H), 7.89 (d, J=8.0 Hz, 2H), 7.48 (d,J=8.0, 1H), 6.90 (s, 1H), 6.79 (d, J=8.5 Hz, 1H), 4.53-4.47 (m, 2H),3.79 (s, 3H), 3.52-3.25 (m, 2H), 3.20-3.13 (m, 2H), 2.13-2.07 (m, 2H);ESI MS m/z 439 [M+H]⁺.

Example 96 Preparation of4-(4-Chloro-2-fluorobenzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepin-2-yl)pyridin-2(1H)-onehydrochloride

A suspension of 4-(4-chloro-2-fluorobenzyloxy)pyridin-2(1H)-one (46 mg,0.18 mmol), tert-butyl2-bromo-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate(76 mg, 0.20 mmol), CuI (41 mg, 0.22 mmol), 8-hydroxyquinoline (5 mg,0.04 mmol) and Cs₂CO₃ (65 mg, 0.20 mmol) in DMSO (10 mL) was degassedunder reduced pressure for 45 min. The suspension was put under N₂ andstirred at 135° C. for 21 h. The suspension was cooled, 9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension wasstirred at 25° C. for 30 min. The suspension was passed through a plugof silica gel, and the filtrate was washed with brine. Activated carbonwas added to the resulting solution, and the resulting suspension wasfiltered. The filtrate was dried over Na₂SO₄ and concentrated underreduced pressure. Flash chromatography on silica gel (Et₂O/(8:1.9:0.1Et₂O/MeOH/NH₄OH) afforded a clear solid. 2 N HCl in Et₂O (100 mL) wasadded to a solution of the clear solid in CH₂Cl₂ (5 mL) under N₂, andthe resulting suspension was stirred at 25° C. for 22 h. The suspensionwas concentrated, and the resulting residue was dissolved in MeOH (1mL). Et₂O was added, and the resulting suspension was filtered. Thesolid was washed with Et₂O and put in a vacuum oven at 40° C. for 1 h toafford 39 mg (44%) of the title compound as a white powder: ¹H NMR (500MHz, DMSO-d₆) δ 8.92 (br s, 2H), 8.16 (d, J=8.0 Hz, 1H), 7.81 (d, J=8.0Hz, 1H), 7.64 (dd, J=8.0, 8.0 Hz, 1H), 7.55 (dd, J=10.0, 2.0 Hz, 1H),7.41-7.35 (m, 2H), 6.15 (dd, J=8.0, 2.5 Hz, 1H), 6.05 (d, J=2.5 Hz, 1H),5.19 (s, 2H), 4.52-4.45 (m, 2H), 3.76 (s, 3H), 3.60-3.31 (m, 2H),3.17-3.11 (m, 2H), 2.13-2.04 (m, 2H); ESI MS m/z 453 [M+H]⁺.

Example 97 Preparation of4-(4-Fluorophenethyl)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)piperazin-2-onedihydrochloride

a) tert-Butyl8-(4-(4-fluorophenethyl)-2-oxopiperazin-1-yl)-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate

tert-Butyl8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate(230 mg, 0.609 mmol) and 4-(4-fluorophenethyl)piperazin-2-one (123 mg,0.534 mmol) were reacted following the procedure for Example 53 (step b)to provide the title compound (199 mg, 71%) as a colorless oil: ESI MSm/z 521 [M+H]⁺.

b)4-(4-Fluorophenethyl)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)piperazin-2-onedihydrochloride

tert-Butyl8-(4-(4-fluorophenethyl)-2-oxopiperazin-1-yl)-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate(199 mg, 0.382 mmol) was reacted following the procedure for Example 53(step b) to provide the title compound (152 mg, 81%) as a white solid:¹H NMR (500 MHz, DMSO-d₆) δ 11.96 (s, 1H), 9.40-9.23 (m, 2H), 7.50 (d,J=8.3 Hz, 1H), 7.38-7.35 (m, 3H), 7.20 (t, J=8.6 Hz, 2H), 6.97 (d, J=8.2Hz, 1H), 4.23-3.79 (br m, 5H), 3.79-3.42 (br m, 8H), 3.40-3.34 (m, 2H),3.29-3.22 (m, 2H), 3.19-3.04 (m, 4H); ESI MS m/z 421 [M+H]⁺; HPLC(Method B) >99% (AUC), t_(R)=10.5 min.

Example 98 Preparation of1-(3,6-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-(4-fluorophenethyl)piperazin-2-onedihydrochloride

4-(4-Fluorophenethyl)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)piperazin-2-onedihydrochloride (50 mg, 0.10 mmol) was reacted following the procedurefor Example 29 to provide the title compound (33 mg, 66%) as a whitesolid: ¹H NMR (500 MHz, DMSO-d₆) δ 11.46 (s, 1H), 10.50 (s, 1H), 7.51(d, J=8.0 Hz, 1H), 7.40-7.33 (m, 3H), 7.25-7.14 (m, 2H), 6.96 (d, J=8.4Hz, 1H), 4.21-3.79 (m, 5H), 3.75-3.39 (m, 7H), 3.38-3.17 (m, 6H),3.17-3.01 (m, 3H), 2.94 (d, J=4.9 Hz, 3H); ESI MS m/z 435 [M+H]⁺; HPLC(Method B) 98.4% (AUC), t_(R)=10.2 min.

Example 99 Preparation of1-(3-Ethyl-6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-(4-fluorophenethyl)piperazin-2-onedihydrochloride

4-(4-Fluorophenethyl)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)piperazin-2-onedihydrochloride (50 mg, 0.10 mmol) was reacted following the procedurefor Example 30 to provide the title compound (31 mg, 63%) as a whitesolid: ¹H NMR (500 MHz, DMSO-d₆) δ 11.44 (s, 1H), 10.16 (s, 1H), 7.51(d, J=7.5 Hz, 1H), 7.41-7.38 (m, 3H), 7.23-7.15 (m, 2H), 6.97 (d, J=8.2Hz, 1H), 4.23-3.79 (m, 5H), 3.71-3.43 (m, 6H), 3.38-3.17 (m, 9H),3.17-3.01 (m, 3H), 1.31 (t, J=7.2 Hz, 3H); ESI MS m/z 449 [M+H]⁺; HPLC(Method B) >99% (AUC), t_(R)=10.5 min.

Example 100 Preparation of4-(4-Chlorobenzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-onehydrochloride

a) 2-Chloro-4-(4-chlorobenzyloxy)pyridine

A mixture of 2-chloro-4-iodopyridine (5.0 g, 21 mmol), 4-chlorobenzylalcohol (3.3 g, 23 mmol), cesium carbonate (8.9 g, 27 mmol), CuI (4.0 g,21 mmol) and phenanthronine (0.76 g, 4.2 mmol) in toluene (20.0 mL) waspurged with nitrogen for 10 min. The reaction mixture was heated at 105°C. overnight and then cooled and diluted with EtOAc. The resultingsolution was washed with brine, passed through a pad of celite andconcentrated under reduced pressure. The resulting residue was purifiedby flash column chromatography (hexanes/EtOAc 100% to 70%) to give thetitle compound (3.0 g, 56%): ¹H NMR (500 MHz, CDCl₃) δ 8.21 (d, J=6.0Hz, 1H), 7.39 (d, J=8.5 Hz, 2H), 7.32 (d, J=8.5 Hz, 2H), 6.90 (d, J=2.0Hz, 1H), 6.80 (dd, J=6.0, 2.0 Hz, 1H), 4.07 (s, 2H).

b) 4-(4-Chlorobenzyloxy)pyridin-2(1)-one (CAS Registry Number191090-84-3) (Wu et al., Tetrahedron Letters 38:3135-3138 (1997), whichis hereby incorporated by reference in its entirety)

A mixture of 2-chloro-4-(4-chlorobenzyloxy)pyridine (3.1 g, 12 mmol) andammonium acetate (4.7 g, 61 mmol) in formic acid (20 mL, 90% in water)and water (20 mL) was heated under reflux for 4 days and thenconcentrated under reduced pressure. The residue was dissolved in DCM,basified with aqueous sodium bicarbonate and filtered. The filtrate wasconcentrated under reduced pressure, and the resulting residue wastriturated with DCM to give the title compound (1.1 g, 39%) as a whitesolid:

¹H NMR (500 MHz, CDCl₃) δ 12.27-12.10 (br s, 1H), 7.37 (d, J=8.0 Hz,2H), 7.33 (d, J=8.5 Hz, 2H), 7.21 (d, J=8.5 Hz, 1H), 6.03 (dd, J=6.5,2.0 H, 1H), 5.92 (d, J=2.0 Hz, 1H), 4.99 (s, 2H).

c)4-(4-Chlorobenzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-onehydrochloride

A suspension of 4-(4-chlorobenzyloxy)pyridin-2(1H)-one (91.0 mg, 0.38mmol), tert-butyl8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)carboxylate (160 mg, 0.42 mmol), 8-hydroxyquinoline (11 mg, 0.072 mmol)and Cs₂CO₃ (137 mg, 0.42 mmol) in DMSO (10.0 mL) was degassed underreduced pressure for 40 min. CuI (87 mg, 0.46 mmol) was added to theabove solution, and the reaction mixture was degassed under reducedpressure for 2×5 min. The reaction mixture was heated at 135° C. undernitrogen overnight. The suspension was cooled, 9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH (10mL) was added, and the resulting suspension wasstirred at 25° C. for 5 min. Celite was added, and the suspension wasstirred for 5 min. The suspension was filtered through Celite, and thefiltrate was washed with brine. The resulting solution was dried overNa₂SO₄ and concentrated under reduced pressure. The residue wasdissolved in dichloromethane (1.0 mL), and HCl (2M in diethyl ether, 5.0mL) was added. The resulting slurry was stirred at room temperatureovernight and concentrated under reduced pressure. Purification bypreparative HPLC followed by preparative TLC (DCM/MeOH/concentratedammonia 96:3.6:0.4) and preparative HPCL afforded the title compound (41mg, 23%) as a white solid: ¹H NMR (500 MHz, CD₃OD) δ 7.58 (d, J=8.5 Hz,1H), 7.57 (d, J=7.5 Hz, 1H), 7.47 (d, J=8.5 Hz, 2H), 7.43 (d, J=8.5 Hz,2H), 7.39 (d, J=1.5 Hz, 1H), 7.01 (dd, J=8.5, 2.0 Hz, 1H), 6.28 (dd,J=8.0, 3.0 Hz, 1H), 6.11 (d, J=2.5 Hz, 1H), 5.17 (s, 2H), 3.74 (s, 3H),3.54 (t, J=5.5 Hz, 2H), 3.48 (t, J=5.5 Hz, 2H), 3.35-3.33 (m, 2H), 3.23(t, J=5.5 Hz, 2H); ESI MS m/z 434 [M+H]⁺.

Example 101 Preparation of1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-phenethylpyrimidin-2(1H)-onehydrochloride

a) (E)-2-Methoxy-4-styrylpyrimidine

A solution of 4-chloro-2-methoxypyrimidine (0.36 g, 2.5 mmol),trans-2-phenylvinylboronic acid (0.56 g, 3.8 mmol) and potassiumcarbonate (0.69 g, 5.0 mmol) in DMSO (8.0 mL) was purged with argon for5 min. 1,1′-Bis(diphenylphosphino)ferrocenedichloropalladium(II) (0.18g, 0.25 mmol) was added to the above solution. The reaction mixture waspurged with argon for 5 min and then heated at 95° C. for 16 h. Thereaction solution was cooled to room temperature, diluted with ethylacetate, washed with water (2×) and brine, dried over sodium sulfate andconcentrated under reduced pressure. The resulting residue was purifiedby flash column chromatography (silica gel hexanes/ethyl acetate 95:5 to60:40) to afford the title compound (0.51 g, 96%) as a yellow solid: ¹HNMR (500 MHz, CDCl₃) δ 8.47 (d, J=5.0 Hz, 1H), 7.92 (d, J=16.0 Hz, 1H),7.61-7.58 (m, 2H), 7.42-7.35 (m, 3H), 7.01 (d, J=16.0 Hz, 1H), 6.94 (d,J=5.0 Hz, 1H), 4.07 (s, 3H).

b) 2-Methoxy-4-phenethylpyrimidine

To a solution of (E)-2-methoxy-4-styrylpyrimidine (0.51 g, 2.4 mmol) inmethanol (25 mL) was added palladium on carbon (0.18 g). The reactionmixture was stirred under hydrogen balloon for 3 days and then filteredthrough a pad of celite. The filtrate was concentrated under reducedpressure to provide the title compound (0.50 g, 97%) as a colorless oil:¹H NMR (500 MHz, CDCl₃) δ 8.35 (d, J=5.0 Hz, 1H), 7.29-7.26 (m, 2H),7.21-7.18 (m, 3H), 6.72 (d, J=5.0 Hz, 1H), 4.02 (s, 3H), 3.08-2.98 (m,4H).

c) 4-Phenethylpyrimidin-2(1H)-one

A solution of 2-methoxy-4-phenethylpyrimidine (0.50 g, 2.3 mmol) inconcentrated HCl (4.0 mL) was heated under reflux for 16 h. The reactionsolution was cooled to room temperature and filtered. The filter cakewas washed with water and dried under reduced pressure to give the titlecompound (0.34 g, 74%) as an off-white solid: ¹H NMR (500 MHz, CD₃OD) δ8.52 (d, J=6.5 Hz, 1H), 7.33-7.24 (m, 5H), 6.78 (d, J=6.0 Hz, 1H),3.12-3.07 (m, 4H).

d) tent-Butyl6-methyl-8-(2-oxo-4-phenethylpyrimidin-1(2H)-yl)-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H) carboxylate

A suspension of 4-phenethylpyrimidin-2(1H)-one (55 mg, 0.28 mmol),tent-butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-]indole-3(6H)carboxylate (0.13 g, 0.34 mmol), 8-hydroxyquinoline (10 mg, 0.07 mmol)and Cs₂CO₃ (0.12 g, 0.36 mmol) in DMSO (4.5 mL) was degassed underreduced pressure for 15 min. CuI (65 mg, 0.34 mmol) was added to theabove solution, and the reaction mixture was degassed under reducedpressure for 5 min. The suspension was heated at 135° C. in a microwavefor 150 min, and then the mixture was cooled and diluted with ethylacetate. The resulting mixture was washed with aqueous LiCl (5%),ammonium hydroxide (2×) and brine. The organic extract was separated,dried over sodium sulfate and concentrated under reduced pressure. Thecrude material was dissolved in DCM, treated with charcoal for 20 minand filtered through a pad of celite. The filtrate was concentratedunder reduced pressure, and the residue was purified by flash columnchromatography (DCM to DCM/MeOH 95:5) to give the title compound (45 mg,32%) as a yellow oil: ¹H NMR (500 MHz, CDCl₃) δ 7.65 (d, J=6.5 Hz, 1H),7.52 (t, J=8.5 Hz, 1H), 7.33-7.26 (m, 5H), 7.24 (t, J=7.0 Hz, 1H), 7.01(t, J=8.5 Hz, 1H), 6.22 (d, J=7.0 Hz, 1H), 3.81-3.65 (m, 4H), 3.65 (s,3H), 3.15-3.12 (m, 2H), 3.07-2.98 (m, 6H), 1.50-1.48 (m, 9H).

e)1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)-4-phenethylpyrimidin-2(1H)-onehydrochloride

To a solution of tent-butyl6-methyl-8-(2-oxo-4-phenethylpyrimidin-1(2H)-yl)-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)carboxylate (44 mg, 0.088 mmol) in dichloromethane (4.0 mL) was addedHCl (2M in diethyl ether, 4.0 mL). The resulting slurry was stirred atroom temperature for 2 days and then concentrated under reducedpressure. The residue was purified by semi-preparative HPLC (PhenomenexLuna C18 (2), 250.0×21.20 mm, 10 micron, H₂O with 0.05% TFA and CH₃CNwith 0.05% TFA). The clean fractions were combined and concentratedunder reduced pressure. The resulting trifluoroacetate salt was treatedwith aqueous sodium carbonate and extracted with EtOAc (2×). Thecombined organic extract was washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure. The free base was converted to theHCl salt using HCl in methanol and lypholized to provide the titlecompound (19.8 mg, 52%) as a light yellow solid: ¹H NMR (500 MHz, CD₃OD)δ 8.03 (d, J=7.0 Hz, 1H), 7.58 (d, J=8.5 Hz, 1H), 7.45 (d, J=2.0 Hz,1H), 7.30-7.28 (m, 4H), 7.22-7.17 (m, 1H), 7.05 (dd, J=8.5, 2.0 Hz, 1H),6.56 (d, J=6.5 Hz, 1H), 3.73 (s, 3H), 3.42-3.34 (m, 4H), 3.27-3.25 (m,2H), 3.17-3.15 (m, 2H), 3.10-3.08 (m, 2H), 3.04-3.02 (m, 2H); ESI MS m/z399 [M+H]⁺.

Example 102 Preparation of4-((3,5-Difluoropyridin-2-yl)methoxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-onehydrochloride a) 2((2-Chloropyridin-4-yloxy)methyl)-3,5-difluoropyridine

(3,5-Difluoropyridin-2-yl)methanol (4.15 g, 28.4 mmol),2-chloro-4-iodopyridine (7.47 g, 31.2 mmol), cesium carbonate (12.0 g,36.3 mmol), CuI (5.40 g, 28.4 mmol) and 1,10-phenanthroline (1.02 g,5.60 mmol) were stirred in toluene (20 mL) and purged with a nitrogenstream for 10 minutes. The mixture was heated to 105° C. for 16 h,allowed cool and filtered through a silica plug eluting with ethylacetate. The filtrate was concentrated, and the residue was purified bycolumn chromatography (80 g ISCO column column eluting with ethylacetate/hexanes; gradient 100% hexanes to 60% ethyl acetate) to yieldthe title compound (3.42 g, 47%) as a yellow oil; ESI MS m/z 257 [M+H]⁺.

b) 4((3,5-Difluoropyridin-2-yl)methoxy)pyridin-2(1H)-one

2((2-Chloropyridin-4-yloxy)methyl)-3,5-difluoropyridine (3.42 g, 13.3mmol) and ammonium acetate (20.5 g, 267 mmol) were heated at 110° C. informic acid (45 mL) for 5 days. The mixture was concentrated to removemost of the liquid and then adjusted to pH 8 with NaHCO₃ solution. Thesolid was filtered off to provide the title compound (2.02 g, 63%) as awhite solid; ESI MS m/z 239 [M+H]⁺.

c) tent-Butyl8-(4-((3,5-difluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)carboxylate

4((3,5-Difluoropyridin-2-yl)methoxy)pyridin-2(1H)-one (100 mg, 0.418mmol) and tent-butyl8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate(206 mg, 0.544 mmol) were reacted following the procedure for Example 2(step d) to provide the title compound (70 mg, 30%) as a brown oil; ESIMS m/z 537 [M +H]⁺.

d)4-((3,5-Difluoropyridin-2-yl)methoxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-one hydrochloride

tert-Butyl8-(4-((3,5-difluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)carboxylate (70 mg, 0.127 mmol) was reacted following the procedure forExample 2 (step e) to provide the title compound (36 mg, 60%) as anorange solid: mp 215-225° C; ¹H NMR (500 MHz, DMSO-d₆) δ 9.24 (s, 2H),8.60 (d, J=2.3 Hz, 1H), 8.08-8.06 (m, 1H), 7.56-7.53 (m, 2H), 7.43 (d,J=1.7 Hz, 1H), 6.95-6.94 (dd, J=8.4, 1.8 Hz, 1H), 6.09-6.05 (m, 2H),5.27 (d, J=1.6 Hz, 2H), 3.69 (s, 3H), 3.37-3.35 (m, 2H), 3.35-3.32 (m,2H), 3.26-3.24 (m, 2H), 3.13-3.11 (m, 2H); ESI MS m/z 437 [M+H]⁺; HPLC(Method B) 96.5% (AUC), t_(R)=13.1 min.

Example 103 Preparation of4-(4-Fluorobenzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-onehydrochloride a) tent-Butyl 8-(4-(4-fluorobenzyloxy)-2-oxopyridin-1(2H)-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4, 3-b]indole-2(1H)-carboxylate

A suspension of 4-(4-fluorobenzyloxy)pyridin-2(1H)one (95 mg, 0.43mmol), tent-butyl8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)carboxylate (180 mg, 0.47 mmol), 8-hydroxyquinoline (13 mg, 0.086 mmol)and Cs₂CO₃ (154 mg, 0.47 mmol) in DMSO (10 mL) was degassed underreduced pressure for 40 min. CuI (98 mg, 0.52 mmol) was added to theabove solution, and the reaction mixture was degassed under reducedpressure for 2×5 min. The reaction mixture was then heated at 135° C.under nitrogen overnight. The reaction suspension was cooled, 9:0.9:0.1CH₂Cl₂/MeOH/NH₄OH (10 mL) was added, and the resulting suspension wasstirred at 25° C. for 5 min. Celite was added, and the suspension wasstirred for 5 min. The suspension was filtered through Celite, and thefiltrate was washed with brine, dried over Na₂SO₄ and concentrated underreduced pressure. The resulting residue was dissolved in DCM and stirredwith charcoal for 10 min. The suspension was filtered, concentrated andpurified to afford the title compound (0.12 g, 54%) as a mixture ofrotamers: ¹H NMR (500 MHz, CDCl₃) δ 7.63 (d, J=8.5 Hz, 0.4H), 7.53 (d,J=8.0 Hz, 0.6H), 7.41 (dd, J=8.0, 6.0 Hz, 2H), 7.33-7.26 (m, 2H), 7.10(t, J=8.5 Hz 2H), 7.00 (d, J=8.0 Hz, 1H), 6.07 (s, 1H), 6.02 (d, J=5.5Hz, 1H), 5.01 (s, 2H), 4.71 (s, 0.7H), 4.63 (s, 1.3H), 3.76 (br s,1.3H), 3.68 (br s, 0.7H), 3.65 (s, 3H), 2.97 (br s, 2H), 2.05-2.03 (m,2H), 1.44 (s, 3.1H), 1.37 (s, 5.9H).

b)4-(4-Fluorobenzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-onehydrochloride

To a solution of tent-butyl8-(4-(4-fluorobenzyloxy)-2-oxopyridin-1(2H)-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)carboxylate (120 mg, 0.23 mmol) in dichloromethane (1.0 mL) was addedHCl (2M in diethyl ether, 5.0 mL). The resulting slurry was stirred atroom temperature overnight and concentrated under reduced pressure. Theresidue was purified by semi-preparative HPLC (Phenomenex Luna C18 (2),250.0×21.20 mm, 10 micron, H₂O with 0.05% TFA and CH₃CN with 0.05% TFA).The clean fractions were combined and concentrated under reducedpressure. The trifluoracetate salt was converted to HCl salt bydissolving in 1.25 M HCl in methanol and concentrating the resultingsolution to dryness. This process was repeated three times to afford thetitle compound (40.0 mg, 38%) as an off-white solid: ¹H NMR (500 MHz,CD₃OD) δ 7.63 (d, J=8.5 Hz, 1H), 7.57 (d, J=7.5 Hz, 1H), 7.51 (dd,J=8.5, 5.5 Hz, 2H), 7.44 (s, 1H), 7.15 (t, J=8.5 Hz, 2H), 7.06 (dd,J=8.5, 2.0 Hz, 1H), 6.28 (dd, J=7.5, 3.0 Hz, 1H), 6.12 (d, J=3.0 Hz,1H), 5.16 (s, 2H), 4.55 (s, 2H), 3.77 (s, 3H), 3.58 (t, J=5.5 Hz, 2H),3.20 (t, J=5.5 Hz, 2H), 2.23-2.19 (m, 2H); ESI MS m/z 418 [M+H]⁺.

Example 104 Preparation of8-(4-((5-Fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-6-methyl-2,3,4,5-tetrahydroazepino[4,3-b]indol-1(6H)-one

8-Bromo-6-methyl-2,3,4,5-tetrahydroazepino[4,3-b]indol-1(6H)-one (100mg, 0.340 mmol) and 4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one(102 mg, 0.510 mmol) were reacted following the procedure for Example 2(step d) to provide the title compound (32 mg, 21%) as a white solid: ¹HNMR (300 MHz, DMSO-d₆) δ 8.53 (d, J=8.6 Hz, 1H), 8.48 (s, 1H), 7.51-7.46(m, 2H), 7.37-7.31 (m, 2H), 7.13-7.17 (dd, J=8.5, 1.8 Hz, 1H), 6.12-6.03(m, 2H), 5.93-5.86 (m, 1H), 5.17 (s, 2H), 3.66 (s, 3H), 3.42-3.34 (m,2H), 3.09 (t, J=6.8 Hz, 2H), 2.28-2.19 (m, 2H); ESI MS m/z 433 [M+H]⁺;HPLC (Method B) 98.7% (AUC), t_(R)=13.8 min.

Example 105 Preparation of4-(4-Chlorobenzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-onehydrochloride a) tent-Butyl 8-(4-(4-chlorobenzyloxy)-2-oxopyridin-1(2H)-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4, 3-b]indole-2(1H)-carboxylate

A suspension of 4-(4-chlorobenzyloxy)pyridin-2(1H)-one (84 mg, 0.38mmol), tent-butyl8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(160 mg, 0.42 mmol), 8-hydroxyquinoline (11 mg, 0.076 mmol) and Cs₂CO₃(137 mg, 0.42 mmol) in DMSO (10 mL) was degassed under reduced pressurefor 40 min. CuI (87.0 mg, 0.42 mmol) was added to the above solution,and the reaction mixture was degassed under reduced pressure for 10 min.The reaction mixture was heated at 135° C. under nitrogen overnight. Thesuspension was cooled, 9:0.9:0.1 CH₂Cl₂/MeOH/NH₄OH (10 mL) was added,and the resulting suspension was stirred at 25° C. for 5 min. Celite wasadded, and the resulting suspension was stirred for 5 min. Thesuspension was filtered through Celite, and the filtrate was washed withbrine, dried over Na₂SO₄ and concentrated under reduced pressure. Theresulting residue was dissolved in DCM and stirred with charcoal for 10min. The suspension was filtered, concentrated and purified by prep-TLC(CH₂Cl₂/MeOH 95:5) to afford the title compound (0.10 g, 49%) as a lightyellow solid and as a mixture of rotamers: ¹H NMR (500 MHz, CDCl₃) δ7.63 (d, J=7.0 Hz, 0.3H), 7.53 (d, J=8.0 Hz, 0.7H), 7.39 (d, J=8.5 Hz,2H), 7.36 (d, J=8.5 Hz, 2H), 7.35-7.27 (m, 2H), 6.99 (d, J=8.5 Hz, 1H),6.05 (s, 1H), 6.03 (dd, J=7.5, 2.0 Hz, 1H), 5.02 (s, 2H), 4.71 (s,0.7H), 4.63 (s, 1.3H), 3.76-3.65 (m, 2H), 3.65 (s, 3H), 2.99-2.97 (m,2H), 2.05-2.00 (m, 2H), 1.44 (s, 3.3H), 1.37 (s, 5.7H).

b)4-(4-Chlorobenzyloxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-onehydrochloride

To a solution of tent-butyl8-(4-(4-chlorobenzyloxy)-2-oxopyridin-1(2H)-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(100 mg, 0.19 mmol) in dichloromethane (20 mL) was trifluoroacetic acid(0.5 mL). The reaction mixture was stirred at room temperature for 2 hand then concentrated under reduced pressure. The residue was purifiedby preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron,H₂O with 0.05% TFA and CH₃CN with 0.05% TFA). The clean fractions werecombined and concentrated under reduced pressure. The trifluoracetatesalt was converted to the HCl salt by dissolving in 1.25 M HCl inmethanol and concentrating the resulting solution to dryness. Thisprocess was repeated three times afforded the title compound (35 mg,39%) as an off-white solid: ¹H NMR (500 MHz, CD₃OD) δ 7.64 (d, J=8.0 Hz,2H), 7.48-7.42 (m, 5H), 7.07 (dd, J=8.0, 2.0 Hz, 1H), 6.37 (dd, J=7.5,2.5 Hz, 1H), 6.17 (d, J=3.0 Hz, 1H), 5.20 (s, 2H), 4.55 (s, 2H), 3.77(s, 3H), 3.59-3.57 (m, 2H), 3.22-3.19 (m, 2H), 2.26-2.18 (m, 2H); ESI MSm/z 434 [M+H]⁺.

Example 106 Preparation of4-((3,5-Difluoropyridin-2-yl)methoxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)pyridin-2(1H)-onehydrochloride a) tent-Butyl 8-(4((3,5-difluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

4-((3,5-Difluoropyridin-2-yl)methoxy)pyridin-2(1H)-one (206 mg, 0.544mmol) and tert-butyl8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(100 mg, 0.418 mmol) were reacted following the procedure for Example 2(step d) to provide the title compound (117 mg, 50%) as a yellow oil;ESI MS m/z 537 [M +H]⁺;

b) 4-((3,5-Difluoropyridin-2-yl)methoxy)-1-(6-methyl-1,2,3,4,5,6-hexahydroazepino[4,3-4]indol-8-yl)pyridin-2(1H)-one hydrochloride

tert-Butyl8-(4-((3,5-difluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(111 mg, 0.208 mmol) was reacted following the procedure for Example 2(step e) to provide the title compound (87 mg, 89%) as a pink solid: mp180-190° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 8.99 (s, 2H), 8.60 (d, J=2.3Hz, 1H), 8.10-8.06 (dt, J=10.2, 2.6 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H),7.56 (d, J=7.3 Hz, 1H), 7.49 (d, J=1.7 Hz, 1H), 7.01-6.99 (dd, J=10.0,2.6 Hz, 1H), 6.09-6.06 (m, 2H), 5.26 (s, 2H), 4.42-4.40 (m, 2H), 3.71(s, 3H), 3.44-3.41 (m, 2H), 3.10-3.08 (m, 2H), 2.09-2.03 (m, 2H); ESI MSm/z 437 [M+H]⁺; HPLC (Method B) 96.5% (AUC), t_(R)=13.6 min.

Example 107 Preparation of1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-phenethylpyrimidin-2(1H)-onehydrochloride a) tert-butyl 6-methyl-8-(2-oxo-4-phenethylpyrimidin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2 (1H) carboxylate

A suspension of 4-phenethylpyrimidin-2(1H)-one (55 mg, 0.28 mmol),tent-butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)carboxylate (0.13 g, 0.34 mmol), 8-hydroxyquinoline (10 mg, 0.07 mmol)and Cs₂CO₃ (0.12 g, 0.36 mmol) in DMSO (4.5 mL) was degassed underreduced pressure for 15 min. CuI (65.0 mg, 0.34 mmol) was added to theabove solution, and the reaction mixture was degassed under reducedpressure for 5 min. The suspension was heated at 135° C. in a microwavefor 150 min. The mixture was then cooled and diluted with ethyl acetate.The resulting mixture was washed sequentially with an aqueous solutionof LiCl (5%) and ammonium hydroxide (1%) (2×) and brine. The organicextract was separated, dried over sodium sulfate and concentrated underreduced pressure. The crude material was dissolved in DCM, treated withcharcoal for 20 min and filtered through a pad of celite. The filtratewas concentrated under reduced pressure, and the residue was purified byflash column chromatography (DCM to DCM/MeOH 95:5) to give the titlecompound (34.0 mg, 25%) as a yellow oil: ¹H NMR (500 MHz, CDCl₃) δ7.67-7.53 (m, 2H), 7.33-7.20 (m, 6H), 7.05-6.98 (m, 1H), 6.22 (d, J=6.5Hz, 1H), 4.71-4.62 (m, 2H), 3.76-3.68 (m, 2H), 3.66 (s, 3H), 3.15-3.12(m, 2H), 3.02-2.96 (m, 4H), 2.08-2.02 (m, 2H), 1.49-1.27 (m, 9H).

b)1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-phenethylpyrimidin-2(1H)-one hydrochloride

To a solution of tert-butyl6-methyl-8-(2-oxo-4-phenethylpyrimidin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)carboxylate (25 mg, 0.068 mmol) in dichloromethane (4.0 mL) was addedHCl (2M in diethyl ether, 4.0 mL). The resulting slurry was stirred atroom temperature for 2 days and then concentrated under reducedpressure. The resulting residue was purified by semi-preparative HPLC.The clean fractions were combined and concentrated under reducedpressure. The resulting trifluoroacetate salt was treated with aqueoussodium carbonate and extracted with EtOAc (2×). The combined organicextract was washed with brine, dried over Na₂SO₄ and concentrated underreduced pressure. The free base was converted to its HCl salt using HClin methanol and lypholized to provide the title compound (18.0 mg, 60%)as a yellow solid: ¹H NMR (500 MHz, CD₃OD) δ 8.17 (d, J=6.5 Hz, 1H),7.67 (d, J=8.0 Hz, 1H), 7.55 (d, J=2.0 Hz, 1H), 7.32-7.26 (m, 4H),7.22-7.18 (m, 1H), 7.15 (dd, J=8.5, 2.0 Hz, 1H), 6.64 (d, J=6.5 Hz, 1H),4.56 (s, 2H), 3.79 (s, 3H), 3.60-3.57 (m, 2H), 3.27-3.20 (m, 2H),3.14-3.06 (m, 4H), 2.23-2.18 (m, 2H); ESI MS m/z 399 [M+H]⁺.

Example 108 Preparation of1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-2(1H)-onehydrochloride a) tent-Butyl6-methyl-8-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-1(2H)-yl)-3,4,5, 6-tetrahydroazepino[4,3-b]indole-2 (1H) carboxylate

A suspension of tert-butyl8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate(105 mg, 0.28 mmol),4-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-2(1H)-one (50 mg, 0.18mmol), 8-hydroxyquinoline (6 mg, 0.04 mmol) and Cs₂CO₃ (0.12 g, 0.37mmol) in DMSO (5.0 mL) was degassed under reduced pressure for 30 min.CuI (61.9 mg, 0.33 mmol) was added to the above solution, and thereaction mixture was degassed under reduced pressure for 5 min.Triethylamine (0.025 mL, 0.18 mmol) was added to the above solution. Theresulting suspension was stirred at 135° C. for 20 h. The reactionmixture was cooled and diluted with EtOAc. The resulting solution waswashed sequentially with aqueous ammonium chloride and aqueous LiCl(5%), dried over sodium sulfate and concentrated under reduced pressure.The resulting crude material was dissolved in DCM, treated with charcoaland purified by preparative TLC (DCM/MeOH 95:5) to afford the titlecompound (55.0 mg, 72%) as a brown yellow solid and as a mixture ofrotamers: ¹H NMR (500 MHz, CDCl₃) δ 9.35 (d, J=1.5 Hz, 1H), 8.75 (d,J=8.0 Hz, 1H), 8.02-7.99 (m,1H), 7.86 (d, J=8.5 Hz, 1H), 7.69 (d, J=8.5Hz, 0.3H), 7.59 (d, J=8.5 Hz, 0.7H), 7.40 (s, 1H), 7.09-7.06 (m, 1H),6.93 (d, J=7.0 Hz, 1H), 4.72 (s, 0.7H), 4.64 (s, 1.3H), 3.79-3.67 (m,2H), 3.69 (s, 3H), 2.99-2.97 (m, 2H), 2.08-2.02 (m, 2H), 1.44 (s, 3.3H),1.38 (s, 5.7H).

b)1-(6-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indol-8-yl)-4-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-2(1H)-one hydrochloride

To a solution of tent-butyl6-methyl-8-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-]indole-2(1H)carboxylate (55 mg, 0.13 mmol) in DCM (10 mL) was added TFA (0.50 mL).The reaction solution was stirred at room temperature for 2 h and thenconcentrated under reduced pressure. The resulting residue was purifiedby semi-preparative HPLC (Phenomenex Luna C18 (2), 250.0×21.20 mm, 10micron, H₂O with 0.05% TFA and CH₃CN with 0.05% TFA). The resulting freebase was converted to the HCl salt using HCl in methanol to afford thetitle compound (23.0 mg, 37%) as a brown-reddish solid: ¹H NMR (500 MHz,CD₃OD) δ 9.47 (d, J=1.5 Hz, 1H), 8.80 (dd, J=6.0,2.0 Hz, 1H), 8.41 (d,J=6.5 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.71 (d, J=8.5 Hz, 1H), 6.64 (d,J=1.5 Hz, 1H), 7.37 (d, J=7.0 Hz, 1H), 7.23 (dd, J=8.5, 2.0 Hz, 1H),4.58 (s, 2H), 3.72 (s, 3H), 3.61-3.58 (m, 2H), 3.24-3.21 (m, 2H),2.27-2.20 (m, 2H); ESI MS m/z 440 [M+H]⁺.

Example 109 Preparation of4-(4-Chlorobenzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)pyridin-2(1H)-onehydrochloride a) tent-Butyl2-(4-(4-chlorobenzyloxy)-2-oxopyridin-1(2H)-yl)-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate

tert-Butyl2-bromo-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate(125 mg, 0.329 mmol) and 4-(4-chlorobenzyloxy)pyridin-2(1H)-one (85 mg,0.36 mmol) were reacted following the procedure for Example 2 (step d)to provide the title compound (123 mg, 70%) as a white solid: ESI MS m/z535 [M+H]⁺.

b)4-(4-Chlorobenzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)pyridin-2(1H)-onehydrochloride

tert-Butyl2-(4-(4-chlorobenzyloxy)-2-oxopyridin-1(2H)-yl)-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate(123 mg, 0.230 mmol) was reacted following the procedure for Example 2(step e) to provide the title compound (93 mg, 86%) as a white solid: ¹HNMR (500 MHz, DMSO-d₆) δ 9.05 (s, 2H), 8.03 (d, J=8.2 Hz, 1H), 7.80 (d,J=7.7 Hz, 1H), 7.50 (s, 4H),7.31 (d, J=8.2 Hz, 1H), 6.17-6.15 (dd,J=7.2, 2.7 Hz, 1H), 5.97 (d, J=2.7 Hz, 1H), 5.17 (s, 2H), 3.73 (s, 3H),3.43-3.37 (m, 2H), 3.37-3.31 (m, 2H), 3.30-3.25 (m, 2H), 3.16-3.11 (m,2H); ESI MS m/z 435 [M+H]⁺; HPLC (Method B) 97.5% (AUC), t_(R)=14.5 min.

Example 110 Preparation of4-(4-Fluorobenzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)pyridin-2(1H)-onehydrochloride a) tent-Butyl2-(4-(4-fluorobenzyloxy)-2-oxopyridin-1(2H)-yl)-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate

tert-Butyl2-bromo-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate(120 mg, 0.316 mmol) and 4-(4-fluorobenzyloxy)pyridin-2(1H)-one (76 mg,0.35 mmol) were reacted following the procedure for Example 2 (step d)to provide the title compound (100 mg, 62%) as a white solid: ESI MS m/z519 [M+H]⁺.

b)4-(4-Fluorobenzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)pyridin-2(1H)-onehydrochloride

tert-Butyl2-(4-(4-fluorobenzyloxy)-2-oxopyridin-1(2H)-yl)-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate(100 mg, 0.192 mmol) was reacted following the procedure for Example 2(step e) to provide the title compound (80 mg, 92%) as a white solid: ¹HNMR (500 MHz, DMSO-d₆) δ 9.03 (s, 2H), 8.06 (d, J=8.2 Hz, 1H), 7.81 (d,J=7.7 Hz, 1H), 7.54-7.41 (m, 2H), 7.30 (d, J=8.2 Hz, 1H), 7.29-7.23 (m,2H), 6.16-6.14 (dd, J=7.2, 2.7 Hz, 1H), 5.99 (d, J=2.6 Hz, 1H), 5.14 (s,2H), 3.73 (s, 3H), 3.43-3.38 (m, 2H), 3.37-3.31 (m, 2H), 3.30-3.26 (m,2H), 3.16-3.11 (m, 2H); ESI MS m/z 419 [M+H]⁺; HPLC (Method B) 95.6%(AUC), t_(R)=13.8 min.

Example 111 Preparation of4-((3,5-Difluoropyridin-2-yl)methoxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)pyridin-2(1H)-onehydrochloride a) tert-Butyl2-(4-(3,5-difluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate

tert-Butyl2-bromo-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate(120 mg, 0.317 mmol) and4((3,5-difluoropyridin-2-yl)methoxy)pyridin-2(1H)-one (83 mg, 0.35 mmol)were reacted following the procedure for Example 2 (step d) to providethe title compound (97 mg, 57%) as a white solid: ESI MS m/z 538 [M+H]⁻.

b)4-(3,5-Difluoropyridin-2-yl)methoxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepin-2-yl)pyridin-2(1H)-onehydrochloride

tert-Butyl2-(4-((3,5-difluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate(97 mg, 0.18 mmol) was reacted following the procedure for Example 2(step e) to provide the title compound (45 mg, 53%) as a white solid: ¹HNMR (500 MHz, DMSO-d₆) δ 9.08 (s, 2H), 8.59 (d, J=2.3 Hz, 1H), 8.09-8.06(dt, J=9.5, 2.4 Hz, 1H), 8.02 (d, J=8.2 Hz, 1H), 7.77 (d, J=7.7 Hz, 1H),7.32 (d, J=8.2 Hz, 1H), 6.15-6.12 (dd, J=7.7, 2.7 Hz, 1H), 6.07 (d,J=2.7 Hz, 1H), 5.28 (s, 2H), 3.73 (s, 3H), 3.42-3.37 (m, 2H), 3.36-3.31(m, 2H), 3.30-3.26 (m, 2H), 3.16-3.11 (m, 2H); ESI MS m/z 438 [M+H]⁺;HPLC (Method B) 98.6% (AUC), t_(R)=12.5 min.

Example 112 Preparation of4-(4-Fluorobenzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepin-2-yl)pyridin-2(1H)-onehydrochloride a) tent-Butyl2-(4-(4-fluorobenzyloxy)-2-oxopyridin-1(2H)-yl)-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate

tert-Butyl 2-bromo-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate (147 mg, 0.386 mmol) and4-(4-fluorobenzyloxy)pyridin-2(1H)-one (93 mg, 0.43 mmol) were reactedfollowing the procedure for Example 2 (step d) to provide the titlecompound (193 mg, 96%) as a yellow oil: ESI MS m/z 519 [M+H]⁺.

b)4-(4-Fluorobenzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepin-2-yl)pyridin-2(1H)-onehydrochloride

tert-Butyl2-(4-(4-fluorobenzyloxy)-2-oxopyridin-1(2H)-yl)-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate(193 mg, 0.372 mmol) was reacted following the procedure for Example 2(step e) to provide the title compound (139 mg, 82%) as a white solid:¹H NMR (500 MHz, DMSO-d₆) δ 8.84 (s, 2H), 8.15 (d, J=8.3 Hz, 1H), 7.81(d, J=7.6 Hz, 1H), 7.55-7.51 (m, 2H), 7.37 (d, J=8.0 Hz, 1H), 7.26 (t,J=9.1 Hz, 2H), 6.17-6.14 (dd, J=7.7, 2.6 Hz, 1H), 5.99 (d, J=2.7 Hz,1H), 5.15 (s, 2H), 4.62-4.50 (m, 2H), 3.76 (s, 3H), 3.49-3.44 (m, 2H),3.16-3.11 (m, 2H), 2.10-2.04 (m, 2H); ESI MS m/z 419 [M+H]⁺; HPLC(Method B) >99% (AUC), t_(R)=13.6 min.

Example 113 Preparation of4-(4-Chlorobenzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepin-2-yl)pyridin-2(1H)-onehydrochloride a) tent-Butyl2-(4-(4-chlorobenzyloxy)-2-oxopyridin-1(2H)-yl)-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate

tert-Butyl2-bromo-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate(110 mg, 0.289 mmol) and 4-(4-chlorobenzyloxy)pyridin-2(1H)-one (75 mg,0.318 mmol) were reacted following the procedure for Example 2 (step d)to provide the title compound (130 mg, 84%) as a colorless oil: ESI MSm/z 535 [M+H]⁺.

b)4-(4-Chlorobenzyloxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepin-2-yl)pyridin-2(1H)-onehydrochloride

tert-Butyl2-(4-(4-chlorobenzyloxy)-2-oxopyridin-1(2H)-yl)-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate(130 mg, 0.243 mmol) was reacted following the procedure for Example 2(step e) to provide the title compound (91 mg, 80%) as a white solid: ¹HNMR (500 MHz, DMSO-d₆) δ 8.91 (s, 2H), 8.16 (d, J=8.2 Hz, 1H), 7.82 (d,J=7.6 Hz, 1H), 7.50 (s, 4H), 7.37 (d, J=8.2 Hz, 1H), 6.18-6.16 (dd,J=7.7, 2.6 Hz, 1H), 5.97 (d, J=2.7 Hz, 1H), 5.17 (s, 2H), 4.49-4.45 (m,2H), 3.76 (s, 3H), 3.49-3.42 (m, 2H), 3.16-3.11 (m, 2H), 2.10-2.04 (m,2H); ESI MS m/z 435 [M+H]⁺; HPLC (Method B) >99% (AUC), t_(R)=14.5 min.

Example 114 Preparation of4-((3,5-Difluoropyridin-2-yl)methoxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepin-2-yl)pyridin-2(1H)-onehydrochloride a) tent-Butyl2-(4-(3,5-difluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate

tert-Butyl2-bromo-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate(120 mg, 0.32 mmol) and4-((3,5-difluoropyridin-2-yl)methoxy)pyridin-2(1H)-one (83 mg, 0.35mmol) were reacted following the procedure for Example 2 (step d) toprovide the title compound (139 mg, 82%) as a white foam: ESI MS m/z 537[M+H]⁺.

b)4-((3,5-Difluoropyridin-2-yl)methoxy)-1-(10-methyl-5,6,7,8,9,10-hexahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepin-2-yl)pyridin-2(1H)-onehydrochloride

tert-Butyl2-(4-((3,5-difluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate (139 mg, 0.259 mmol) was reactedfollowing the procedure for Example 2 (step e) to provide the titlecompound (62 mg, 51%) as a white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 8.92(s, 2H), 8.59 (d, J=2.3 Hz, 1H), 8.17 (d, J=8.3 Hz, 1H), 8.09-8.05 (dt,J=9.5, 2.3 Hz, 1H), 7.81 (d, J=7.7 Hz, 1H), 7.36 (d, J=8.2 Hz, 1H),6.15-6.12 (dd, J=7.7, 2.7 Hz, 1H), 6.08 (d, J=2.7 Hz, 1H), 5.28 (s, 2H),4.49-4.45 (m, 2H), 3.73 (s, 3H), 3.48-3.43 (m, 2H), 3.15-3.11 (m, 2H),2.11-2.05 (m, 2H); ESI MS m/z 438 [M+H]⁺; HPLC (Method B) 96.8% (AUC),t_(R)=12.2 min.

Example 115 Binding Assay for Human Melanin-Concentrating Hormone(MCH-1) Receptor

Evaluation of the affinity of compounds for the human MCH-1 receptor wasaccomplished using4-(3,4,5-tritritiumbenzyloxy)-1-(1-(2-(pyrrolidin-1-yl)ethyl)-1H-indazol-5-yl)pyridin-2(1H)-oneand membranes prepared from stable CHO-K1 cells expressing the humanMCH-1 receptor obtained from Euroscreen (Batch 1138). Cell membranehomogenates (8.92 μg protein) were incubated for 60 min at 25° C. with1.4 nM of the [³H]-labeled compound in the absence or presence of thetest compound in 50 mM Tris-HCl buffer, pH 7.4. Nonspecific binding wasdetermined in the presence of 50 μM1-(5-(4-cyanophenyl)bicyclo[3.1.0]hexan-2-yl)-3-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-(4-methylpiperazin-1-yl)propyl)urea.Following incubation, the samples were filtered rapidly under vacuumthrough Skatron 11731 filters, pre-soaked in 0.5% polyethylenimine, andwashed with ice-cold 50 mM Tris-HCl buffer, pH 7.4, (wash setting 9,9,0)using a Skatron cell harvester. The filters were counted forradioactivity in a liquid scintillation counter (Tri-Carb 2100TR,Packard) using a scintillation cocktail (Ultima Gold MV, Perkin Elmer).

The results are expressed as a percent inhibition of the controlradioligand specific binding. The IC₅₀ value (concentration causing ahalf-maximal inhibition of control specific binding) and Hillcoefficient (n_(H)) were determined by non-linear regression analysis ofthe competition curve using Hill equation curve fitting. The inhibitionconstant (K_(i)) was calculated from the Cheng Prusoff equation:(K_(i)=IC₅₀/(1+(L/K_(D))), where L=concentration of radioligand in theassay, and K_(D)=affinity of the radioligand for the receptor.

By methods as described above, the compounds listed in Table 1 weresynthesized and tested for biological activity.

TABLE 1 Compounds Tested for Biological Activity Ex. MCH₁ Mass No.Structure K_(i) (nM) Spec ¹H NMR Data 2

14.4 440 ¹H NMR (500 MHz, DMSO-d₆) δ 9.03 (br s, 2H), 8.70 (d, J = 9.0Hz, 1H), 8.46 (d, J = 9.0 Hz, 1H), 7.90 (d, J = 7.0 Hz, 1H), 7.62-7.59(m, 2H), 7.38 (s, 1H), 7.17 (d, J = 6.5 Hz, 1H), 7.08 (d, J = 9.0 Hz,1H), 3.72 (s, 3H), 3.43- 3.30 (m, 4H), 3.28-3.25 (m, 2H), 3.17-3.11 (m,2H) 3

10.1 439 ¹H NMR (500 MHz, DMSO-d₆) δ 9.15 (s, 1H), 9.00 (br s, 2H), 8.40(d, J = 8.5 Hz, 1H), 8.34 (d, J = 8.5 Hz, 1H), 7.83 (d, J = 7.0 Hz, 1H),7.61-7.56 (m, 2H), 7.28 (d, J = 2.0 Hz, 1H), 7.08-7.05 (m, 2H), 3.72 (s,3H), 3.43- 3.23 (m, 6H), 3.16-3.11 (m, 2H) 4

7.1 439 ¹H NMR (500 MHz, DMSO-d₆) δ 9.20 (d, J = 1.5 Hz, 1H), 9.15-9.02(m, 2H), 8.49 (dd, J = 8.0, 2.0 Hz, 1H), 8.06 (d, J = 8.5 Hz, 1H), 7.84(d, J = 7.3 Hz, 1H), 7.60-7.53 (m, 2H), 7.06 (dd, J = 8.5, 1.5 Hz, 1H),7.00 (d, J = 2.0 Hz, 1H), 6.80 (dd, J = 7.3, 2.0 Hz, 1H), 3.72 (s, 3H),3.42-3.37 (m, 2H), 3.36-3.24 (m, 4H), 3.16-3.12 (m, 2H) 5

11.8 469 ¹H NMR (500 MHz, DMSO-d₆) δ 9.20 (br s, 2H), 8.89 (s, 1H), 8.19(d, J = 8.3 Hz, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.58 (d, J = 7.5 Hz, 1H),7.52 (d, J = 8.0 Hz, 1H), 7.44 (s, 1H), 6.95 (d, J = 8.0 Hz, 1H), 6.14(d, J = 7.5 Hz, 1H), 6.01 (s, 1H), 5.35 (s, 2H), 3.69 (s, 3H), 3.41-3.29(m, 4H), 3.28-3.22 (m, 2H), 3.14-3.10 (m, 2H) 6

131 440 ¹H NMR (500 MHz, DMSO-d₆) δ 9.51 (s, 2H), 9.10 (br s, 2H), 7.89(d, J = 7.0 Hz, 1H), 7.62-7.56 (m, 2H), 7.12 (s, 1H), 7.05 (d, J = 8.5Hz, 1H), 6.86 (d, J = 7.0 Hz, 1H), 3.72 (s, 3H), 3.42- 3.33 (m, 4H),3.29-3.24 (m, 2H), 3.16-3.12 (m, 2H) 7

6.0 386 ¹H NMR (500 MHz, DMSO-d₆) δ 11.18 (s, 1H), 9.06 (br s, 2H),7.57- 7.35 (m, 7H), 7.25 (s, 1H), 6.90 (d, J = 8.0 Hz, 1H), 6.11-6.07(m, 1H), 5.96 (s, 1H), 5.15 (s, 2H), 3.45-3.30 (m, 4H), 3.20-3.15 (m,2H), 3.12-3.06 (m, 2H) 8

148 426 ¹H NMR (500 MHz, DMSO-d₆) δ 11.27 (s, 1H), 9.09 (br s, 2H), 8.69(d, J = 9.0 Hz, 1H), 8.46 (d, J = 9.0 Hz, 1H), 7.89 (d, J = 7.3 Hz, 1H),7.56 (d, J = 8.5 Hz, 1H), 7.40 (s, 1H), 7.36 (s, 1H), 7.16 (d, J = 7.3Hz, 1H), 7.04 (d, J = 8.5 Hz, 1H), 3.41-3.25 (m, 4H), 3.23-3.17 (m, 2H),3.14-3.09 (m, 2H) 9

1371 425 ¹H NMR (500 MHz, DMSO-d₆) δ 11.26 (br s, 1H), 9.15 (br s, 1H),9.08- 9.00 (m, 2H), 8.40-8.32 (m, 2H), 7.81 (d, J = 7.2 Hz, 1H), 7.55(d, J = 8.4 Hz, 1H), 7.38 (d, J = 1.5 Hz, 1H), 7.27 (d, J = 1.8 Hz, 1H),7.08-7.01 (m, 2H), 3.41-3.29 (m, 4H), 3.21-3.14 (m, 2H), 3.13-3.07 (m,2H) 10

13.4 420 ¹H NMR (500 MHz, DMSO-d₆) δ 9.10-8.92 (m, 2H), 8.64 (d, J = 2.5Hz, 1H), 7.99 (d, J = 3.0 Hz, 1H), 7.85 (ddd, J = 8.5, 8.5, 3.0 Hz, 1H),7.71 (dd, J = 8.5, 4.0 Hz, 1H), 7.55-7.51 (m, 2H), 7.08 (dd, J = 8.0,2.0 Hz, 1H), 6.52 (d, J = 2.5 Hz, 1H), 5.29 (s, 2H), 3.69 (s, 3H),3.42-3.32 (m, 4H), 3.27-3.22 (m, 2H), 3.14-3.10 (m, 2H) 11

49.0 385 ¹H NMR (500 MHz, DMSO-d₆) δ 9.27 (br s, 2H), 9.03 (s, 1H),8.47-8.40 (m, 1H), 7.81 (d, J = 7.0 Hz, 1H), 7.71- 7.64 (m, 1H), 7.57(d, J = 8.5 Hz, 1H), 7.53 (d, J = 1.5 Hz, 1H), 7.04 (dd, J = 8.5, 2.0Hz, 1H), 6.95 (br s, 1H), 6.78 (dd, J = 7.0, 2.0 Hz, 1H), 3.71 (s, 3H),3.41-3.31 (m, 4H), 3.29-3.25 (m, 2H), 3.17-3.12 (m, 2H), 2.66 (s, 3H) 12

11.4 424 ¹H NMR (500 MHz, DMSO-d₆) δ 11.25 (s, 1H), 9.15 (br s, 2H),8.00 (d, J = 8.5 Hz, 2H), 7.88 (d, J = 8.5 Hz, 2H), 7.78 (d, J = 7.5 Hz,1H), 7.54 (d, J = 8.5 Hz, 1H), 7.37 (d, J = 2.0 Hz, 1H), 7.01 (dd, J =8.5, 2.0 Hz, 1H), 6.85 (d, J = 2.0 Hz, 1H), 6.70 (dd, J = 7.0, 2.0 Hz,1H), 3.40-3.31 (m, 4H), 3.26-3.18 (m, 2H), 3.09-3.14 (m, 2H) 13

10.3 405 ¹H NMR (500 MHz, DMSO-d₆) δ 11.18 (s, 1H), 9.11 (br s, 2H),8.62 (d, J = 3.0 Hz, 1H), 7.83 (ddd, J = 9.0, 9.0, 3.0 Hz, 1H), 7.65(dd, J = 9.0, 5.0 Hz, 1H), 7.56 (d, J = 7.5 Hz, 1H), 7.49 (d, J = 8.5Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.90 (dd, J = 8.0, 2.0 Hz, 1H), 6.11(d, J = 8.0, 2.5 Hz, 1H), 5.96 (d, J = 2.5 Hz, 1H), 5.21 (s, 2H), 3.38-3.29 (m, 4H), 3.20-3.16 (s, 2H), 3.11- 3.07 (m, 2H) 14

9.6 428 ¹H NMR (500 MHz, DMSO-d₆) δ 10.07 (br s, 1H), 7.59-7.35 (m, 8H),6.95 (dd, J = 8.5, 1.5 Hz, 1H), 6.10 (dd, J = 7.5, 2.5 Hz, 1H),6.01-5.96 (m, 1H), 5.15 (s, 2H), 3.76-3.05 (m, 13H), 1.31 (t, J = 7.0Hz, 3H) 15

10.4 442 ¹H NMR (500 MHz, DMSO-d₆) δ 9.89 (br s, 1H), 7.58-7.52 (m, 2H),7.49- 7.35 (m, 6H), 6.96 (dd, J = 8.5, 2.0 Hz, 1H), 6.10 (dd, J = 7.5,2.5 Hz, 1H), 5.96 (d, J = 3.0 Hz, 1H), 5.15 (s, 2H), 3.77-3.62 (m, 7H),3.42-3.24 (m, 4H), 3.18-3.11 (m, 1H), 1.37-1.31 (m, 6H) 16

13.7 461 ¹H NMR (500 MHz, DMSO-d₆) δ 9.95 (br s, 1H), 8.62 (d, J = 3.0Hz, 1H), 7.83 (ddd, J = 8.5, 8.5, 3.0 Hz, 1H), 7.65 (dd, J = 9.0, 5.0Hz, 1H), 7.57- 7.52 (m, 2H), 7.44 (d, J = 2.0 Hz, 1H), 6.95 (dd, J =8.5, 2.0 Hz, 1H), 6.13 (dd, J = 8.0, 3.0 Hz, 1H), 5.96 (d, J = 2.5 Hz,1H), 5.22 (s, 2H), 3.78-3.62 (m, 6H), 3.43-3.11 (m, 6H), 1.48-1.39 (m,6H) 17

7.2 428 ¹H NMR (500 MHz, DMSO-d₆) δ 11.19 (s, 1H), 9.71 (br s, 1H),7.55- 7.36 (m, 7H), 7.26 (d, J = 2.0 Hz, 1H), 6.91 (dd, J = 8.0, 1.5 Hz,1H), 6.08 (dd, J = 7.5, 3.0 Hz, 1H), 5.96 (d, J = 3.0 Hz, 1H), 5.14 (s,2H), 3.75-3.61 (m, 3H), 3.36-3.05 (m, 6H), 1.36-1.30 (m, 6H) 18

11.8 400 ¹H NMR (500 MHz, DMSO-d₆) δ 9.04 (s, 2H), 7.59-7.55 (m, 2H),7.48-7.41 (m, 5H), 7.38-7.36 (m, 1H), 6.97 (dd, J = 8.5, 2.0 Hz, 1H),6.10 (dd, J = 7.5, 2.5 Hz, 1H), 5.97 (d, J = 2.5 Hz, 1H), 5.15 (s, 2H),4.53 (s, 2H), 3.74 (s, 3H), 3.49-3.47 (m, 2H), 2.97 (t, J = 5.0 Hz, 2H),1.99-1.97 (m, 2H) 19

14.8 419 ¹H NMR (500 MHz, DMSO-d₆) δ 8.62 (d, J = 3.0 Hz, 1H), 8.19 (brs, 1H), 7.84-7.80 (m, 1H), 7.66-7.64 (m, 1H), 7.58-7.51 (m, 2H), 7.45(d, J = 1.5 Hz, 1H), 6.95 (dd, J = 8.0, 3.0 Hz, 1H), 6.12 (dd, J = 7.5,2.5 Hz, 1H), 5.96 (d, J = 3.0 Hz, 1H), 5.21 (s, 2H), 4.39 (s, 2H), 3.71(s, 3H), 3.38-3.36 (m, 2H), 2.95-2.93 (m, 2H), 1.93-1.92 (m, 2H) 20

242 439 ¹H NMR (500 MHz, DMSO-d₆) δ 9.15 (s, 1H), 9.12 (br s, 2H),8.40-8.34 (m, 2H), 7.84 (d, J = 7.5 Hz, 1H), 7.64 (d, J = 8.5 Hz, 1H),7.62 (d, J = 1.5 Hz, 1H), 7.28 (d, J = 2.0 Hz, 1H), 7.10- 7.06 (m, 2H),4.55 (s, 2H), 3.77 (s, 3H), 3.50-3.49 (m, 2H), 3.01-2.98 (m, 2H),2.00-1.98 (m, 2H) 21

4.7 400 ¹H NMR (500 MHz, DMSO-d₆) δ 8.96 (s, 2H), 7.64 (d, J = 8.0 Hz,1H), 7.55 (d, J = 7.5 Hz, 1H), 7.48-7.41 (m, 5H), 7.38-7.36 (m, 1H),6.99 (dd, J = 8.5, 2.0 Hz, 1H), 6.10 (dd, J = 7.5, 2.5 Hz, 1H), 5.96 (d,J = 3.0 Hz, 1H), 5.15 (s, 2H), 4.44-4.43 (m, 2H), 3.71 (s, 3H),3.45-3.43 (m, 2H), 3.09 (t, J = 6.0 Hz, 2H), 2.06-2.04 (m, 2H) 22

11.2 419 ¹H NMR (500 MHz, DMSO-d₆) δ 9.17 (s, 2H), 8.62 (s, 1H), 8.19(d, J = 8.0 Hz, 1H), 7.85-7.81 (m, 1H), 7.67-7.63 (m, 1H), 7.58 (d, J =7.5 Hz, 1H), 7.48 (d, J = 1.5 Hz, 1H), 6.99 (dd, J = 8.5, 1.5 Hz, 1H),6.14 (dd, J = 7.5, 2.5 Hz, 1H), 5.97 (d, J = 3.0 Hz, 1H), 5.22 (s, 2H),4.43-4.41 (m, 2H), 3.71 (s, 3H), 3.43-3.39 (m, 2H), 3.09 (t, J = 5.0 Hz,2H), 2.07-2.05 (m, 2H) 23

4.7 439 ¹H NMR (500 MHz, DMSO-d₆) δ 9.15 (s, 1H), 8.89 (s, 2H), 8.39(dd, J = 8.5, 2.0 Hz, 1H), 8.34 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 7.5Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.62 (d, J = 1.5 Hz, 1H), 7.28 (d, J= 1.5 Hz, 1H), 7.11 (dd, J = 8.0, 1.5 Hz, 1H), 7.07 (d, J = 7.5, 2.0 Hz,1H), 4.47 (s, 2H), 3.74 (s, 3H), 3.47-3.45 (m, 2H), 3.11 (t, J = 5.0 Hz,2H), 2.08-2.06 (m, 2H) 24

6.4 469 ¹H NMR (500 MHz, DMSO-d₆) δ 9.13 (s, 2H), 8.89 (s, 1H), 8.19 (d,J = 8.0 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 8.5 Hz, 1H),7.59 (d, J = 7.5 Hz, 1H), 7.48 (d, J = 1.5 Hz, 1H), 6.99 (dd, J = 8.5,1.5 Hz, 1H), 6.15 (dd. J = 7.5, 2.5 Hz, 1H), 6.01 (d, J = 2.5 Hz, 1H),5.35 (s, 2H), 4.42 (s, 2H), 3.71 (s, 3H), 3.44-3.42 (m, 2H), 3.10-3.09(m, 2H), 2.07-2.06 (m, 2H) 25

42.3 440 ¹H NMR (500 MHz, DMSO-d₆) δ 9.51 (s, 2H), 8.93 (s, 2H), 7.89(d, J = 7.5 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.60 (d, J = 1.5 Hz, 1H),7.12-7.09 (m, 2H), 6.87 (dd, J = 7.5, 2.0 Hz, 1H), 4.47 (s, 2H), 3.74(s, 3H), 3.46-3.40 (m, 2H), 3.12-3.11 (m, 2H), 2.08-2.07 (m, 2H) 26

6.1 438 ¹H NMR (500 MHz, DMSO-d₆) δ 9.01 (s, 2H), 8.01 (d, J = 8.5 Hz,2H), 7.88 (d, J = 8.0 Hz, 2H), 7.80 (d, J = 7.0 Hz, 1H), 7.69 (d, J =8.5 Hz, 1H), 6.60 (d, J = 2.0 Hz, 1H), 7.10 (d, J = 8.5, 2.0 Hz, 1H),6.86 (d, J = 2.0 Hz, 1H), 6.72 (dd, J = 7.5, 2.5 Hz, 1H), 4.55- 4.46 (m,2H), 3.73 (s, 3H), 3.46-3.45 (m, 2H), 3.11 (t, J = 5.5 Hz, 2H),2.08-2.06 (m, 2H) 27

5.3 439 ¹H NMR (500 MHz, DMSO-d₆) δ 9.50 (s, 2H), 9.20 (d, J = 2.0 Hz,1H), 8.50 (dd, J = 8.0, 2.0 Hz, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.86 (d,J = 7.0 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.59 (d, J = 1.5 Hz, 1H),7.09 (dd, J = 8.5, 2.0 Hz, 1H), 7.00 (d, J = 2.0 Hz, 1H), 6.80 (d, J =7.5, 2.0 Hz, 1H), 4.42-4.41 (m, 2H), 3.73 (s, 3H), 3.43-3.41 (m, 2H),3.11 (t, J = 6.0 Hz, 2H), 2.10-2.08 (m, 2H) 28

10.9 440 ¹H NMR (500 MHz, DMSO-d₆) δ 9.03 (s, 2H), 8.71 (d, J = 9.0 Hz,1H), 8.46 (d, J = 8.5 Hz, 1H), 7.91 (d, J = 7.0 Hz, 1H), 7.71 (d, J =8.5 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.17(dd, J = 7.0, 2.0 Hz, 1H), 7.13 (dd, J = 8.5, 1.5 Hz, 1H), 4.46-4.45 (m,2H), 3.75 (s, 3H), 3.46- 3.44 (m, 2H), 3.12 (t, J = 5.5 Hz, 2H),2.08-2.07 (m, 2H) 29

5.0 414 ¹H NMR (500 MHz, DMSO-d₆) δ 10.02 (br s, 1H), 7.67 (d, J = 8.0Hz, 1H), 7.56 (d, J = 7.5 Hz, 1H), 7.49- 7.36 (m, 6H), 7.01 (dd, J =8.5, 2.0 Hz, 1H), 6.10 (dd, J = 7.5, 2.5 Hz, 1H), 5.96 (d, J = 2.5 Hz,1H), 5.15 (s, 2H), 4.73-4.71 (m, 1H), 4.52-4.47 (m, 1H), 3.72 (s, 3H),3.68-3.63 (m, 1H), 3.44-3.41 (m, 1H), 3.16-3.03 (m, 2H), 2.81-2.80 (m,3H), 2.17-2.01 (m, 2H) 30

5.0 428 ¹H NMR (500 MHz, DMSO-d₆) δ 10.34 (br s, 1H), 7.68 (d, J = 8.5Hz, 1H), 7.56 (d, J = 7.5 Hz, 1H), 7.47- 7.41 (m, 5H), 7.39-7.35 (m,1H), 6.99 (dd, J = 8.0, 1.0 Hz, 1H), 6.09 (dd, J = 7.5, 2.5 Hz, 1H),5.96 (d, J = 2.5 Hz, 1H), 5.15 (s, 2H), 4.51 (s, 2H), 3.71 (s, 3H),3.47-3.44 (m, 2H), 3.09-3.08 (m, 2H), 2.97-2.95 (m, 2H), 2.08-2.05 (m,2H), 1.22 (t, J = 6.5 Hz, 3H) 31

9.4 442 ¹H NMR (500 MHz, DMSO-d₆) δ 9.92 (br s, 1H), 7.73 (d, J = 8.5Hz, 1H), 7.57 (d, J = 7.5 Hz, 1H), 7.50-7.35 (m, 6H), 7.02 (dd, J = 8.0,1.5 Hz, 1H), 6.10 (dd, J = 7.5, 2.5 Hz, 1H), 5.97 (d, J = 3.0 Hz, 1H),5.15 (s, 2H), 4.65-4.53 (m, 2H), 3.72 (s, 3H), 3.57- 3.47 (m, 3H), 3.11(t, J = 6.0 Hz, 2H), 2.24-2.07 (m, 2H), 1.34-1.30 (m, 6H) 32

4.9 416 ¹H NMR (500 MHz, DMSO-d₆) δ 8.98 (br s, 2H), 7.75-7.67 (m, 4H),7.58 (s, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 8.5 Hz, 1H), 6.76(s, 1H), 6.68 (d, J = 7.0 Hz, 1H), 4.45 (s, 2H), 3.74 (s, 3H), 3.46-3.45(m, 2H), 3.12-3.10 (m, 2H), 2.54 (s, 3H), 2.07-2.05 (m, 2H) 33

17.5 385 ¹H NMR (500 MHz, DMSO-d₆) δ 9.10 (br s, 2H), 9.04 (s, 1H), 8.44(s, 1H), 7.82 (d, J = 7.0 Hz, 1H), 7.70-7.68 (m, 2H), 7.58 (s, 1H), 7.09(d, J = 8.0 Hz, 1H), 6.96 (s, 1H), 6.79 (d, J = 7.0 Hz, 1H), 4.45. (s,2H), 3.74 (s, 3H), 3.45-3.44 (m, 2H), 3.11-3.09 (m, 2H), 2.66 (s, 3H),2.08-2.07 (m, 2H) 34

10.6 415 ¹H NMR (500 MHz, DMSO-d₆) δ 9.17 (s, 2H), 8.89 (s, 1H), 8.51(d, J = 8.0 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H),7.61 (d, J = 7.5 Hz, 1H), 7.47 (d, J = 1.5 Hz, 1H), 6.98 (dd, J = 8.5,1.5 Hz, 1H), 6.14 (dd, J = 8.0, 2.5 Hz, 1H), 6.03 (d, J = 2.0 Hz, 1H),5.33 (s, 2H), 4.44-4.41 (m, 2H), 3.71 (s, 3H), 3.44-3.42 (m, 2H), 3.10-3.08 (m, 2H), 2.76 (s, 3H), 2.08-2.04 (m, 2H) 35

5.8 386 ¹H NMR (500 MHz, DMSO-d₆) δ 11.45 (s, 1H), 8.90 (s, 2H), 7.61(d, J = 8.5 Hz, 1H), 7.54 (d, J = 7.5 Hz, 1H), 7.48-7.36 (m, 5H), 7.28(d, J = 2.0 Hz, 1H), 6.95 (dd, J = 8.0, 2.0 Hz, 1H), 6.08 (dd, J = 7.5,3.0 Hz, 1H), 5.95 (d, J = 2.5 Hz, 1H), 5.14 (s, 2H), 4.42-4.41 (m, 2H),3.47-3.45 (s, 2H), 3.03 (t, J = 5.0 Hz, 2H), 2.01-1.99 (m, 2H) 36

12.2 425 ¹H NMR (500 MHz, DMSO-d₆) δ 11.51 (s, 1H), 9.14 (s, 1H), 8.81(s, 2H), 8.39 (dd, J = 8.5, 2.0 Hz, 1H), 8.34 (d, J = 8.5 Hz, 1H), 7.82(d, J = 7.5 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.41 (d, J = 2.0 Hz, 1H),7.26 (d, J = 2.0 Hz, 1H), 7.08-7.04 (m, 2H), 4.44 (s, 2H), 3.49-3.47 (m,2H), 3.06-3.04 (m, 2H), 2.03-2.01 (m, 2H) 37

29.2 426 ¹H NMR (500 MHz, DMSO-d₆) δ 11.54 (s, 1H), 8.90 (s, 2H), 8.70(d, J = 9.0 Hz, 1H), 8.46 (d, J = 9.0 Hz, 1H), 7.89 (d, J = 7.5 Hz, 1H),7.69 (d, J = 8.5 Hz, 1H), 7.43 (d, J = 1.5 Hz, 1H), 7.36 (d, J = 2.0 Hz,1H), 7.16 (dd, J = 7.0, 2.0 Hz, 1H), 7.08 (dd, J = 8.5, 2.0 Hz, 1H),4.44 (s, 2H), 3.48-3.46 (m, 2H), 3.05 (t, J = 5.5 Hz, 2H), 2.03- 2.01(m, 2H) 38

100 414 ¹H NMR (500 MHz, DMSO-d₆) δ 8.29 (d, J = 8.5 Hz, 1H), 7.57 (d, J= 8.0 Hz, 1H), 7.53 (t, J = 5.5 Hz, 1H), 7.49-7.35 (m, 6H), 7.00 (dd, J= 8.5, 2.0 Hz, 1H), 6.10 (dd, J = 7.5, 2.5 Hz, 1H), 5.97 (d, J = 2.5Hz,1H), 5.15 (s, 2H), 3.68 (s, 3H), 3.21-3.10 (m, 2H), 3.12 (t, J = 6.5 Hz,2H), 2.08-2.07 (m, 2H) 39

16.8 420 ¹H NMR (500 MHz, DMSO-d₆) δ 8.97 (s, 2H), 8.63 (d, J = 2.5 Hz,1H), 7.99 (d, J = 3.0 Hz, 1H), 7.87-7.83 (m, 1H), 7.72-7.69 (m, 1H),7.64 (d, J = 8.5 Hz, 1H), 7.57 (d, J = 2.0 Hz, 1H), 7.13 (dd, J = 8.5,1.5 Hz, 1H), 6.52 (d, J = 3.0 Hz, 1H), 5.29 (s, 2H), 4.44- 4.43 (m, 2H),3.72 (s, 3H), 3.45-3.43 (m, 2H), 3.10 (t, J = 5.5 Hz, 2H), 2.07-2.05 (m,2H) 40

7.2 419 ¹H NMR (500 MHz, DMSO-d₆) δ 9.25 (s, 2H), 8.62 (d, J = 3.0 Hz,1H), 7.84- 7.80 (m, 1H), 7.66-7.64 (m, 1H), 7.56 (dd, J = 7.5 Hz, 1H),7.51 (d, J = 8.5 Hz, 1H), 7.42 (s, 1H), 6.94 (dd, J = 8.5, 1.5 Hz, 1H),6.12 (dd, J = 7.5, 2.5 Hz, 1H), 5.96 (d, J = 2.5 Hz, 1H), 5.12 (s, 2H),3.68 (s, 3H), 3.37-3.32 (m, 4H), 3.26-3.25 (m, 2H), 3.13-3.12 (m, 2H) 41

10.0 438 ¹H NMR (500 MHz, DMSO-d₆) δ 9.29 (s, 2H), 8.00 (d, J = 8.5 Hz,2H), 7.88 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 7.0 Hz, 1H), 7.57 (d, J =8.5 Hz, 1H), 7.55 (d, J = 1.0 Hz, 1H), 7.05 (dd, J = 8.5, 1.5 Hz, 1H),6.86 (d, J = 1.5 Hz, 1H), 6.71 (dd, J = 7.0, 2.0 Hz, 1H), 3.71 (s, 3H),3.39-3.33 (m, 4H), 3.28-3.27 (m, 2H), 3.16-3.13 (m, 2H) 42

17.8 447 ¹H NMR (500 MHz, DMSO-d₆) δ 10.86 (s, 1H), 8.61 (d, J = 2.5 Hz,1H), 7.82-7.81 (m, 1H), 7.66-7.63 (m, 1H), 7.55 (d, J = 8.0 Hz, 1H),7.40 (d, J = 8.5 Hz, 1H), 7.14 (s, 1H), 6.82 (d, J = 7.0 Hz, 1H), 6.09(dd, J = 7.5, 3.0 Hz, 1H), 5.95 (d, J = 3.0 Hz, 1H), 5.20 (s, 2H),3.02-2.98 (m, 1H), 2.86-2.85 (m, 2H), 2.76 (m, 6H), 1.02 (d, J = 6.5 Hz,6H) 43

8.9 400 ¹H NMR (500 MHz, DMSO-d₆) δ 9.34 (br s, 2H), 7.55-7.37 (m, 8H),6.94 (dd, J = 8.0, 1.0 Hz, 1H), 6.09 (dd, J = 9.0 Hz, 1.0, 1H), 5.96 (s,1H), 5.15 (s, 2H), 3.68 (s, 3H), 3.36-3.26 (m, 6H), 3.14-3.12 (m, 2H) 44

11.6 414 ¹H NMR (500 MHz, CD₃OD) δ 7.58 (dd, J = 8.5 Hz, 3.0 Hz, 2H),7.46 (dd, J = 8.0 Hz, 2.0 Hz, 2H), 7.43-7.39 (m, 3H), 7.37-7.35 (m, 1H),7.01 (dd, J = 8.5, 2.0 Hz, 1H), 6.31 (dd, J = 7.5, 2.5 Hz, 1H), 6.13 (d,J = 1.5 Hz, 1H), 5.18 (s, 2H), 3.81-3.75 (m, 2H), 3.73 (s, 3H),3.60-3.42 (m 2H), 3.41-3.32 (m, 2H); 3.20-3.10 (m, 2H), 3.08 (s, 3H) 45

26 415 ¹H NMR (500 MHz, DMSO-d₆) δ 9.23 (br s, 2H), 8.81 (s, 1H),8.40-8.25 (m, 1H), 7.82-7.75 (m, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.52 (d,J = 8.5 Hz, 1H), 7.42 (d, J = 2.0, 1H), 6.94 (dd, J = 8.5, 2.0 Hz, 1H),6.12 (dd, J = 8.0, 3.0 Hz, 1H), 6.02 (d, J = 2.5 Hz, 1H), 5.28 (s, 2H),3.69 (s, 3H), 3.41-3.29 (m, 4H), 3.28- 3.22 (m, 2H), 3.15-3.10 (m, 2H),2.68 (s, 3H) 46

47 481 ¹H NMR (500 MHz, DMSO-d₆) δ 9.20 (s, 1H), 8.49 (dd, J = 8.0, 2.0Hz, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 7.0 Hz, 1H), 7.55 (d, J= 8.5 Hz, 1H), 7.53-7.50 (m, 1H), 7.04-6.99 (m, 2H), 6.79 (dd, J = 7.0,2.0 Hz, 1H), 3.85- 3.65 (m, 7H), 3.14-2.93 (m, 4H), 2.14 (s, 1.2H), 2.09(s, 1.8H) 47

74 470 ¹H NMR (500 MHz, DMSO-d₆) δ 9.02-8.91 (m, 3H), 8.23 (d, J = 8.5Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 8.00 (d, J = 2.5, 1H), 7.55-7.51 (m,2H), 7.09 (dd, J = 8.5, 2.0 Hz, 1H), 6.56 (d, J = 3.0 Hz, 1H), 5.42 (s,2H), 3.69 (s, 3H), 3.44-3.28 (m, 4H), 3.27-3.21 (m, 2H), 3.13-3.09 (m,2H) 48

60 461 ¹H NMR (500 MHz, DMSO-d₆) δ 8.62 (d, J = 3.0 Hz, 1H), 7.84 (ddd,J = 9.0, 9.0, 3.0 Hz, 1H), 7.66 (dd, J = 8.5, 4.5 Hz, 1H), 7.57 (d, J =8.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.38 (dd, J = 3.0, 1.5 Hz, 1H),6.92-6.88 (m, 1H), 6.12 (dd, J = 7.5, 3.0 Hz, 1H), 5.96 (d, J = 2.5 Hz,1H), 5.22 (s, 2H), 3.82-3.76 (m, 2H), 3.75-3.63 (m, 5H), 3.10 (t, J =5.5, 1H), 3.05-2.98 (m, 2H), 2.93 (t, J = 5.5, 1H), 2.13 (s, 1.5H), 2.08(s, 1.5H) 49

17 439 ¹H NMR (500 MHz, DMSO-d₆) δ 9.10 (br s, 2H), 8.40 (d, J = 8.0 Hz,2H), 8.38 (d, J = 7.0 Hz, 1H), 7.95 (d, J = 8.5 Hz, 2H), 7.65 (d, J =1.5, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.27 (d, J = 7.0 Hz, 1H), 7.14 (dd,J = 8.0, 1.5 Hz, 1H), 3.72 (s, 3H), 3.43-3.32 (m, 4H), 3.29-3.24 (m,2H), 3.16-3.12 (m, 2H) 50

7.4 435 ¹H NMR (500 MHz, DMSO-d₆) δ 9.14 (br s, 2H), 8.78 (d, J = 2.5Hz, 1H), 8.03 (dd, J = 8.5, 2.5 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.57(d, J = 7.5 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 1.5 Hz, 1H),6.94 (dd, J = 8.0, 1.5 Hz, 1H), 6.14 (dd, J = 7.5, 3.0 Hz, 1H), 5.95 (d,J = 2.5 Hz, 1H), 5.23 (s, 2H), 3.69 (s, 3H), 3.40-3.30 (m, 4H),3.26-3.22 (m, 2H), 3.13-3.09 (m, 2H) 51

24 468 ¹H NMR (500 MHz, DMSO-d₆) δ 9.02 (br s, 2H), 7.74 (d, J = 2.0 Hz,1H), 7.66 (d, J = 8.5 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.54-7.50 (m,2H), 7.45 (d, J = 1.5 Hz, 1H), 6.96 (dd, J = 8.5, 2.0 Hz, 1H), 6.10 (dd,J = 7.5, 3.0 Hz, 1H), 6.00 (d, J = 3.0 Hz, 1H), 5.19 (s, 2H), 3.69 (s,3H), 3.42-3.31 (m, 4H), 3.26-3.22 (m, 2H), 3.13-3.09 (m, 2H) 52

7.8 436 ¹H NMR (500 MHz, DMSO-d₆) δ 9.02 (br s, 2H), 7.67 (dd, J = 15.0,9.0 Hz, 1H), 7.54 (d, J = 7.5 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.44(d, J = 1.5 Hz, 1H), 7.35 (ddd, J = 10.5, 10.5, 2.0 Hz, 1H), 7.18 (ddd,J = 8.5, 8.5, 2.5 Hz, 1H), 6.95 (dd, J = 8.5, 2.0 Hz, 1H), 6.07 (dd, J =7.5, 3.0 Hz, 1H), 6.04 (d, J = 3.0 Hz, 1H), 5.15 (s, 2H), 3.69 (s, 3H),3.41-3.31 (m, 4H), 3.26-3.22 (m, 2H), 3.14-3.10 (m, 2H) 53

13 437 ¹H NMR (500 MHz, DMSO-d₆) δ 11.54 (br s, 1H), 9.16 (br s, 2H),7.54-7.32 (m, 6H), 6.96 (d, J = 8.0 Hz, 1H), 4.21-3.44 (m, 9H),3.42-3.05 (m, 12H) 54

112 428 ¹H NMR (500 MHz, DMSO-d₆) δ 10.99 (s, 1H), 7.54 (d, J = 7.5 Hz,1H), 7.49-7.35 (m, 6H), 7.19 (dd, J = 2.5, 2.5 Hz, 1H), 6.88-6.83 (m,1H), 6.07 (dd, J = 8.0, 2.5 Hz, 1H), 5.95 (d, J = 2.5, 1H), 5.14 (s,2H), 3.76-3.65 (m, 4H), 3.06-3.02 (m, 1H), 2.97-2.91 (m, 2H), 2.87-2.82(m, 1H), 2.12 (s, 3H) 55

12 452 ¹H NMR (500 MHz, DMSO-d₆) δ 9.21 (br s, 2H), 7.63 (dd, J = 8.0,8.0 Hz, 1H), 7.57-7.50 (m, 3H), 7.43 (d, J = 1.5 Hz, 1H), 7.39 (dd, J =8.5, 2.0 Hz, 1H), 6.95 (dd, J = 8.5, 2.0 Hz, 1H), 6.08 (dd, J = 7.5, 3.0Hz, 1H), 6.02 (d, J = 2.5 Hz, 1H), 5.18 (s, 2H), 3.69 (s, 3H), 3.41-3.31(m, 4H), 3.28-3.22 (m, 2H), 3.16-3.09 (m, 2H) 56

27 469 ¹H NMR (500 MHz, DMSO-d₆) δ 9.14 (br s, 2H), 8.69 (s, 1H), 8.37(s, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.44 (s,1H), 6.95 (d, J = 8.5 Hz, 1H), 6.09 (dd, J = 7.5, 2.5 Hz, 1H), 6.01 (s,1H), 5.30 (s, 2H), 3.69 (s, 3H), 3.42-3.30 (m, 4H), 3.28-3.22 (m, 2H),3.17-3.09 (m, 2H) 57

7.3 418 ¹H NMR (500 MHz, CD₃OD) δ 7.59 (d, J = 8.5 Hz, 2H), 7.50 (dd, J= 8.0, 5.5 Hz, 2H), 7.40 (s, 1H), 7.15 (t, J = 8.5 Hz, 2H), 7.01 (d, J =8.5 Hz, 1H), 6.30 (t, J = 6.5 Hz, 1H), 6.14 (br s, 1H), 5.16 (s, 2H),3.74 (s, 3H), 3.54 (t, J = 5.5 Hz, 2H), 3.48 (t, J = 5.5 Hz, 2H), 3.34(t, J = 5.5 Hz, 2H), 3.24 (t, J = 5.5 Hz, 2H) 58

163 440 ¹H NMR (500 MHz, CD₃OD) δ 9.48 (s, 1H), 8.80 (d, J = 8.5 Hz,1H), 8.38 (d, J = 6.5 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.66 (d, J =8.5 Hz, 1H), 7.59 (d, J = 1.0 Hz, 1H), 7.36 (d, J = 7.0 Hz, 1H), 7.18(dd, J = 8.5, 1.5 Hz, 1H), 3.78 (s, 3H), 3.56 (t, J = 5.5 Hz, 2H), 3.50(t, J = 5.5 Hz, 2H), 3.37 (t, J = 5.5 Hz, 2H), 3.26 (t, J = 5.5 Hz, 2H)59

44 404 ¹H NMR (500 MHz, CD₃OD) δ 8.86 (d, J = 5.5 Hz, 1H), 8.49-8.46 (m,1H), 8.02 (d, J = 1.0 Hz, 1H), 7.90 (t, J = 6.4 Hz, 1H), 7.60 (d, J =8.0 Hz, 1H), 7.44 (d, J = 1.5 Hz, 1H), 7.08 (dd, J = 8.5, 2.0 Hz, 1H),4.54 (s, 2H), 4.13 (s, 2H), 4.09 (t, J = 5.5 Hz, 2H), 3.80 (t, J = 5.0Hz, 2H), 3.75 (s, 3H), 3.73 (t, J = 5.0 Hz, 2H), 3.63-3.56 (m, 4H),3.20-3.17 (m, 2H), 2.13-2.09 (m, 2H) 60

21 470 ¹H NMR (500 MHz, DMSO-d₆) δ 8.91 (d, J = 1.5 Hz, 1H), 8.87 (s,2H), 8.22 (dd, J = 8.5, 1.5 Hz, 1H), 8.02-8.00 (m, 2H), 7.64 (d, J = 8.5Hz, 1H), 7.57 (d, J = 1.5 Hz, 1H), 7.13 (dd, J = 8.5, 2.0 Hz, 1H ), 6.56(d, J = 3.0 Hz, 1H), 5.41 (s, 2H), 4.44 (s, 2H), 3.72 (s, 3H), 3.47-3.43(m, 2H), 3.10 (t, J = 5.5 Hz, 2H), 2.08-2.04 (m, 2H) 61

57 461 ¹H NMR (500 MHz, DMSO-d₆) δ 8.62 (d, J = 3.0 Hz, 1H), 7.83 (ddd,J = 8.5, 8.5, 3.0 Hz, 1H), 7.66-7.49 (m, 3H), 7.39 (dd, J = 21.0, 2.0Hz, 1H), 6.93 (ddd, J = 22.5, 8.0, 1.5 Hz, 1H), 6.11 (dd, J = 7.5, 2.5Hz, 1H), 5.96 (dd, J = 5.0, 3.0 Hz, 1H), 5.21 (s, 2H), 4.69-4.68 (m,2H), 3.78-3.75 (m, 2H), 3.67-3.65 (m, 3H), 3.03-2.96 (m, 2H), 2.09-1.90(m, 5H) 62

60 481 ¹H NMR (500 MHz, DMSO-d₆) δ 9.19 (s, 1H), 8.49 (dd, J = 8.0, 2.0Hz, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.88-7.83 (m, 1H), 7.72-7.49 (m, 2H),7.07-6.99 (m, 2H), 6.80-6.78 (m, 1H), 4.72-4.70 (m, 2H), 3.79-3.76 (m,2H), 3.69-3.68 (m, 3H), 3.05- 2.98 (m, 2H), 2.02-1.90 (m, 5H) 63

5 435 ¹H NMR (500 MHz, CD₃OD) δ 8.59 (d, J = 2.4 Hz, 1H), 7.95-7.91 (dd,J = 8.4, 2.4 Hz, 1H), 7.62-7.58 (m, 3H), 7.41 (d, J = 1.6 Hz, 1H),7.05-7.04 (dd, J = 8.4, 1.6 Hz, 1H), 6.34-6.30 (dd, J = 7.6, 2.7 Hz,1H), 6.11 (d, J = 2.7 Hz, 1H), 5.26 (s, 2H), 4.46 (s, 2H), 3.75 (s, 3H),3.53-3.49 (m, 2H), 3.19- 3.17 (m, 2H), 2.19-2.12 (m, 2H) 64

4.6 437 ¹H NMR (500 MHz, DMSO-d₆) δ 9.14-8.91 (s, 2H), 7.57 (d, J = 8.7Hz, 1H), 7.40-7.30 (m, 5H), 6.98 (d, J = 8.4 Hz, 1H), 4.42-4.35 (m, 2H),3.79-3.69 (m, 5H), 3.46-3.36 (m, 2H), 3.26-3.18 (m, 2H), 3.10-3.02 (m,2H), 2.97-2.76 (m, 4H), 2.72-2.61 (m, 2H), 2.10-1.97 (m, 2H) 65

11 468 ¹H NMR (500 MHz, DMSO-d₆) δ 9.20-9.10 (s, 2H), 7.74 (d, J = 2.1Hz, 1H), 7.68-7.63 (m, 2H), 7.56 (d, J = 7.6 Hz, 1H), 7.52-7.51 (dd, J =8.2, 2.0 Hz, 1H), 7.49 (d, J = 1.6 Hz, 1H), 7.01-6.98 (dd, J = 8.4, 1.8Hz, 1H), 6.12-6.09 (dd, J = 7.6, 2.7 Hz, 1H), 6.01 (d, J = 2.7 Hz, 1H),5.19 (s, 2H), 4.46-4.39 (s, 2H), 3.71 (s, 3H), 3.47-3.30 (m, 2H),3.14-3.03 (m, 2H), 2.12-1.99 (m, 2H) 66

7.3 436 ¹H NMR (500 MHz, DMSO-d₆) δ 9.14-8.77 (s, 2H), 7.69-7.63 (m,2H), 7.55 (d, J = 7.5 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.37-7.32 (dt,J = 10.3, 2.5 Hz, 1H), 7.19-7.15 (m, 1H), 7.01-6.99 (dd, J = 8.3, 1.8Hz, 1H), 6.08-6.06 (dd, J = 7.5, 2.8 Hz, 1H), 6.04 (d, J = 2.8 Hz, 1H),5.15 (s, 2H), 4.55-4.24 (m, 2H), 3.72 (s, 3H), 3.50-3.41 (m, 2H),3.10-3.08 (m, 2H), 2.14-1.91 (m, 2H) 67

22 469 ¹H NMR (500 MHz, DMSO-d₆) δ 9.21-8.98 (s, 2H), 8.69 (d, J = 2.1Hz, 1H), 8.37 (d, J = 2.1 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.55 (d, J= 7.6 Hz, 1H), 7.49 (d, J = 1.8 Hz, 1H), 7.01-6.99 (dd, J = 8.8, 1.8 Hz,1H), 6.10-6.09 (dd, J = 7.6, 2.8 Hz, 1H), 6.01 (d, J = 2.8 Hz, 1H), 5.30(s, 2H), 4.43-4.42 (m, 2H), 3.71 (s, 3H), 3.48-3.39 (m, 2H), 3.10-3.07(m, 2H), 2.14-1.93 (m, 2H) 68

8.2 452 ¹H NMR (500 MHz, DMSO-d₆) δ 9.22-9.04 (s, 2H), 7.65-7.61 (m,2H), 7.57-7.53 (m, 2H), 7.48 (d, J = 1.8 Hz, 1H), 7.39-7.37 (dd, J =8.1, 1.8 Hz, 1H), 7.00-6.97 (dd, J = 8.2, 1.8 Hz, 1H), 6.09-6.07 (dd, J= 7.6, 2.8 Hz, 1H), 6.03 (d, J = 2.8 Hz, 1H), 5.17 (s, 2H), 4.43-4.41(m, 2H), 3.71 (s, 3H), 3.38-3.33 (m, 2H), 3.18-3.08 (m, 2H), 2.10-2.06(m, 2H) 69

12 454 ¹H NMR (500 MHz, DMSO-d₆) δ 10.14 (s, 1H), 8.71 (d, J = 8.9 Hz,1H), 8.47 (d, J = 9.1 Hz, 1H), 7.92 (d, J = 7.2 Hz, 1H), 7.75 (d, J =8.4 Hz, 1H), 7.65 (d, J = 1.7 Hz, 1H), 7.38 (d, J = 1.8 Hz, 1H),7.18-7.17 (dd, J = 7.2, 2.0 Hz, 1H), 7.15-7.14 (dd, J = 8.4, 1.8 Hz,1H), 4.76 (d, J = 14.3 Hz, 1H), 4.54-4.50 (dd, J = 14.5, 6.5 Hz, 1H),3.75 (s, 3H), 3.70-3.64 (m, 1H), 3.46- 3.40 (m, 1H), 3.16-3.05 (m, 2H),2.81 (d, J = 5.0 Hz, 3H), 2.20-2.14 (m, 1H), 2.09-2.00 (m, 1H) 70

8.8 433 ¹H NMR (500 MHz, CD₃OD) δ 8.63 (d, J = 2.7 Hz, 1H), 7.90-7.88(dd, J = 8.1, 2.8 Hz, 1H), 7.81-7.79 (m, 2H), 7.71 (d, J = 8.4 Hz, 1H),7.51 (d, J = 1.7 Hz, 1H), 7.11-7.09 (dd, J = 8.4, 1.8 Hz, 1H), 6.57-6.55(dd, J = 7.5, 2.8 Hz, 1H), 6.34 (d, J = 2.8 Hz, 1H), 5.39 (s, 2H), 4.80(d, J = 14.8 Hz, 1H), 4.59 (d, J = 14.8 Hz, 1H), 3.85-3.75 (m, 4H),3.56-3.51 (m, 1H), 3.26-3.15 (m, 2H), 2.79 (s, 3H), 2.57-2.31 (m, 1H),2.19-2.14 (m, 1H) 71

8.5 483 ¹H NMR (500 MHz, DMSO-d₆) δ 10.52-10.04 (s, 1H), 8.88 (d, J =1.3 Hz, 1H), 8.20-8.18 (dd, J = 8.1, 1.5 Hz, 1H), 7.99 (d, J = 8.1 Hz,1H), 7.69 (d, J = 8.2 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.50 (d, J =1.8 Hz, 1H), 7.02-7.00 (dd, J = 8.6, 1.8 Hz, 1H), 6.16-6.14 (dd, J =7.6, 2.8 Hz, 1H), 6.02 (d, J = 2.8 Hz, 1H), 5.35 (s, 2H), 4.72 (d, J =14.2 Hz, 1H), 4.51-4.47 (dd, J = 14.6, 6.5 Hz, 1H), 3.72 (s, 3H),3.70-3.61 (m, 1H), 3.44-3.38 (m, 1H), 3.11-3.04 (m, 2H), 2.79 (d, J =4.9 Hz, 3H), 2.17-2.14 (m, 1H), 2.06- 2.03 (m, 1H) 72

7.5 473 ¹H NMR (500 MHz, DMSO-d₆) δ 11.0-10.35 (s, 1H), 8.61 (d, J = 2.9Hz, 1H), 7.85-7.81 (dt, J = 8.8, 2.9 Hz, 1H), 7.66-7.63 (m, 2H), 7.58(d, J = 7.6 Hz, 1H), 7.50 (d, J = 1.7 Hz, 1H), 7.01-6.99 (dd, J = 8.4,1.9 Hz, 1H), 6.14-6.12 (dd, J = 7.6, 1.8 Hz, 1H), 5.96 (d, J = 2.8 Hz,1H), 5.22 (s, 2H), 4.51 (d, J = 14.2 Hz, 1H), 4.14-4.12 (dd, J = 14.4,5.2 Hz, 1H), 3.72 (s, 3H), 3.67-3.62 (m, 1H), 3.56-3.52 (m, 1H), 3.30-3.25 (m, 1H), 3.12-3.10 (m, 2H), 2.43-2.39 (m, 1H), 2.29-2.25 (m, 1H),2.15-2.04 (m, 4H), 1.70-1.68 (m, 1H), 1.62-1.68 (m, 1H) 73

9.4 447 ¹H NMR (500 MHz, DMSO-d₆) δ 10.00-9.95 (s, 1H), 8.62 (s, 1H),7.85- 7.80 (dt, J = 8.8, 3.0 Hz, 1H), 7.66-7.64 (m, 2H), 7.58 (d, J =7.6 Hz, 1H), 7.48 (s, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.14-6.12 (dd, J =7.6, 2.2 Hz, 1H), 5.97 (d, J = 2.8 Hz, 1H), 5.21 (s, 2H), 4.72-4.34 (m,2H), 3.71 (s, 3H), 3.69-3.63 (m, 2H), 3.14-2.68 (m, 4H), 2.16-1.95 (m,2H), 1.39-1.15 (m, 3H) 74

10 435 ¹H NMR (500 MHz, CD₃OD) δ 7.63 (d, J = 8.0 Hz, 1H), 7.41 (s, 1H),7.34-7.32 (m, 2H), 7.08-7.04 (m, 3H), 4.75 (d, J = 14.1 Hz, 1H), 4.54(d, J = 14.4 Hz, 1H), 4.00-3.85 (m, 2H), 3.80-3.70 (m, 5H), 3.60-3.47(m, 2H), 3.18-3.15 (m, 5H), 3.03-2.90 (m, 3H), 2.95 (s, 3H), 2.39-2.30(m, 1H), 2.20-2.15 (m, 1H) 75

14 475 ¹H NMR (500 MHz, CD₃OD) δ 7.58 (d, J = 8.4 Hz, 1H), 7.40 (s, 1H),7.32- 7.29 (m, 2H), 7.05-7.02 (m, 3H), 4.61 (d, J = 14.6 Hz, 1H), 4.42(d, J = 14.6 Hz, 1H), 3.84-3.79 (m, 3H), 3.75 (s, 3H), 3.69-3.65 (m,2H), 3.63-3.34 (m, 3H), 3.42-2.78 (m, 7H), 2.51-2.38 (m, 1H), 2.38-2.25(m, 3H), 2.25-2.03 (m, 2H), 1.87-1.76 (m, 2H) 76

9.8 449 ¹H NMR (500 MHz, CD₃OD) δ 7.61 (d, J = 8.4 Hz, 1H), 7.39 (d, J =1.3 Hz, 1H), 7.31-7.29 (m, 2H), 7.05-7.02 (m, 3H), 4.72 (d, J = 14.9 Hz,1H), 4.62 (d, J = 14.9 Hz, 1H), 3.92-3.79 (m, 2H), 3.86-3.79 (m, 5H),3.59-3.47 (m, 2H), 3.26-3.17 (m, 6H), 3.00-2.81 (m, 4H), 2.40-2.24 (m,1H), 2.24-2.00 (m, 1H), 1.38 (t, J = 7.3 Hz, 3H) 77

11 401 ¹H NMR (500 MHz, DMSO-d₆) δ 9.19 (s, 2H), 8.02 (d, J = 8.5 Hz,1H), 7.79 (d, J = 7.5 Hz, 1H), 7.48-7.41 (m, 4H), 7.38 (d, J = 7.5 Hz,1H), 7.30 (d, J = 8.0 Hz, 1H), 6.16 (dd, J = 7.5, 2.5 Hz, 1H), 5.98 (d,J = 2.5 Hz, 1H), 5.16 (s, 2H), 3.73 (s, 3H), 3.39-3.38 (m, 2H),3.33-3.31 (m, 2H), 3.30-3.28 (m, 2H), 3.14 (t, J = 5.5 Hz, 2H) 78

29 440 ¹H NMR (500 MHz, DMSO-d₆) δ 9.28 (s, 2H), 9.21 (d, J = 2.0 Hz,1H), 8.50 (dd, J = 8.5, 2.0 Hz, 1H), 8.10-8.04 (m, 3H), 7.41 (d, J = 8.0Hz, 2H), 7.03 (d, J = 1.5 Hz, 1H), 6.85 (dd, J = 7.5, 3.5 Hz, 1H), 5.98(d, J = 2.5 Hz, 1H), 3.76 (s, 3H), 3.41-3.40 (m, 2H), 3.33- 3.31 (m, 2H,overlaps with solvent), 3.17 (t, J = 5.5 Hz, 2H) 79

235 441 ¹H NMR (500 MHz, DMSO-d₆) δ 9.10 (s, 2H), 8.71 (d, J = 9.0 Hz,1H), 8.47 (d, J = 9.0 Hz, 1H), 8.12-8.10 (m, 2H), 7.44 (d, J = 8.0 Hz,1H), 7.40 (d, J = 2.0 Hz, 1H), 7.23 (dd, J = 7.0, 2.0 Hz, 1H), 3.77 (s,3H), 3.46-3.41 (m, 2H), 3.38-3.34 (m, 2H), 3.32-3.30 (m, 2H, overlappedwith solvent), 3.17 (t, J = 6.0 Hz, 2H) 80

69 440 ¹H NMR (500 MHz, DMSO-d₆) δ 9.19 (s, 2H), 9.15 (dd, J = 1.0, 1.0Hz, 1H), 8.41-8.35 (m, 2H), 8.09 (d, J = 8.5 Hz, 1H), 8.05 (d, J = 7.0Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.30 (d, J = 2.0 Hz, 1H), 7.12 (dd, J= 7.0, 2.0 Hz, 1H), 3.76 (s, 3H), 3.42-3.40 (m, 2H), 3.36-3.32 (m, 2H),3.30-3.28 (m, 2H, overlaps with H₂O), 3.17 (t, J = 6.5 Hz, 2H) 81

33 420 ¹H NMR (500 MHz, DMSO-d₆) δ 9.43 (s, 2H), 8.62 (d, J = 2.0 Hz,1H), 8.02 (d, J = 8.5 Hz, 1H), 7.84-7.80 (m, 2H), 7.67-7.64 (m, 1H),7.30 (d, J = 8.5 Hz, 1H), 6.19 (dd, J = 7.5, 2.5 Hz, 1H), 5.98 (d, J =2.5 Hz, 1H), 5.23 (s, 2H), 3.73 (s, 3H), 3.40-3.37 (m, 2H), 3.34-3.30(m, 4H), 3.18-3.14 (m, 2H) 82

53 421 ¹H NMR (500 MHz, DMSO-d₆) δ 9.12 (s, 2H), 8.64 (d, J = 3.0 Hz,1H), 8.06 (d, J = 8.0 Hz, 1H), 7.98 (d, J = 2.5 Hz, 1H), 7.85 (ddd, J =11.5, 8.5, 2.5 Hz, 1H), 7.72-7.69 (m, 1H), 7.15 (d, J = 8.5 Hz, 1H),6.51 (d, J = 3.0 Hz, 1H), 5.30 (s, 2H), 3.71 (s, 3H), 3.45- 3.39 (m,2H), 3.38-3.31 (m, 2H), 3.30-3.28 (m, 2H), 3.15-3.14 (m, 2H) 83

13 437 ¹H NMR (500 MHz, DMSO-d₆) δ 9.04 (br s, 2H), 8.03 (d, J = 8.5 Hz,1H), 7.79 (d, J = 8.0 Hz, 1H), 7.67 (dd, J = 15.5, 8.5 Hz, 1H), 7.35(ddd, J = 10.0, 10.0, 2.5 Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 7.18 (ddd,J = 8.5, 8.5, 2.0 Hz, 1H), 6.14 (dd, J = 8.0, 3.0 Hz, 1H), 6.06 (d, J =2.5 Hz, 1H), 5.17 (s, 2H), 3.74 (s, 3H), 3.59-3.32 (m, 4H), 3.31- 3.26(m, 2H), 3.17-3.14 (m, 2H) 84

11 453 ¹H NMR (500 MHz, DMSO-d₆) δ 9.00 (br s, 2H), 8.03 (d, J = 8.5 Hz,1H), 7.79 (d, J = 8.0 Hz, 1H), 7.64 (dd, J = 8.0, 8.0 Hz, 1H), 7.54 (dd,J = 10.0, 1.5 Hz, 1H), 7.39 (br d, J = 8.5 Hz, 1H), 7.32 (d, J = 8.0 Hz,1H), 6.15 (dd, J = 8.0, 3.0 Hz, 1H), 6.05 (d, J = 2.5 Hz, 1H), 5.19 (s,2H), 3.74 (s, 3H), 3.60-3.32 (m, 4H), 3.31-3.26 (m, 2H), 3.17-3.12 (m,2H) 85

11 436 ¹H NMR (500 MHz, DMSO-d₆) δ 9.17 (br s, 2H), 8.68 (s, 1H),8.07-8.00 (m, 2H), 7.81 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H),7.31 (d, J = 8.0 Hz, 1H), 6.20 (br d, J = 6.0 Hz, 1H), 5.97 (br s, 1H),5.25 (s, 2H), 3.73 (s, 3H), 3.44-3.21 (m, 6H), 3.19-3.11 (m, 2H) 86

16 455 ¹H NMR (500 MHz, DMSO-d₆) δ 10.65 (br s, 1H), 8.04 (d, J = 8.0Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.50-7.35 (m, 5H), 7.33 (d, J = 8.5Hz, 1H), 6.17 (dd, J = 7.5, 2.0 Hz, 1H), 5.99 (d, J = 2.0 Hz, 1H), 5.17(s, 2H), 3.99-3.88 (m, 1H), 3.73 (s, 3H), 3.61-3.52 (m, 2H), 3.41-3.17(m, 4H), 3.15-3.07 (m, 2H), 2.41-2.25 (m, 4H), 1.83-1.60 (m, 2H) 87

6.9 429 ¹H NMR (500 MHz, DMSO-d₆) δ 10.26 (br s, 1H), 8.04 (d, J = 8.5Hz, 1H), 7.79 (d, J = 7.5 Hz, 1H), 7.50- 7.36 (m, 5H), 7.32 (d, J = 8.0Hz, 1H), 6.17 (dd, J = 7.5, 2.5 Hz, 1H), 5.99 (d, J = 2.5 Hz, 1H), 5.17(s, 2H), 3.77- 3.62 (m, 5H), 3.50-3.09 (m, 8H), 1.32 (t, J = 7.0 Hz, 3H)88

8.7 415 ¹H NMR (500 MHz, DMSO-d₆) δ 10.35-10.20 (m, 1H), 8.04 (d, J =8.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.50-7.35 (m, 5H), 7.32 (d, J =8.0 Hz, 1H), 6.17 (dd, J = 7.5, 2.5 Hz, 1H), 5.99 (d, J = 2.5 Hz, 1H),5.17 (s, 2H), 3.74 (s, 3H), 3.73-3.63 (m, 2H), 3.43-3.22 (m, 5H),3.12-3.03 (m, 1H), 2.97 (br s, 3H) 89

15 440 ¹H NMR (500 MHz, DMSO-d₆) δ 9.21 (d, J = 2.0 Hz, 1H), 9.04 (s,2H), 8.50 (dd, J = 8.0, 2.0 Hz, 1H), 8.22 (d, J = 8.0 Hz, 1H), 8.09-8.05(m, 2H), 7.47 (d, J =8.0 Hz, 1H), 7.03 (d, J = 2.0 Hz, 1H), 6.85 (dd, J= 7.5, 2.0 Hz, 1H), 4.49 (s, 2H), 3.80 (s, 3H), 3.49- 3.46 (m, 2H),3.17-3.15 (m, 2H), 2.09-2.07 (m, 2H) 90

6.4 401 ¹H NMR (500 MHz, DMSO-d₆) δ 9.20 (s, 2H), 8.16 (d, J = 8.0 Hz,1H), 7.81 (d, J = 8.0 Hz, 1H), 7.48-7.41 (m, 4H), 7.38-7.34 (m, 2H),6.17 (dd, J = 7.5, 2.5 Hz, 1H), 5.98 (d, J = 2.5 Hz, 1H), 5.17 (s, 2H),4.46 (s, 2H), 3.75 (s, 3H), 3.44-3.43 (m, 2H), 3.14-3.12 (m, 2H),2.09-2.07 (m, 2H) 91

15 420 ¹H NMR (500 MHz, DMSO-d₆) δ 9.15 (s, 2H), 8.62 (d, J = 3.0 Hz,1H), 8.16 (d, J = 8.5 Hz, 1H), 7.88-7.80 (m, 2H), 7.67-7.64 (m, 1H),7.35 (d, J = 8.0 Hz, 1H), 6.19 (dd, J = 8.0, 2.5 Hz, 1H), 5.99 (d, J =2.5 Hz, 1H), 5.23 (s, 2H), 4.46 (s, 2H), 3.75 (s, 3H), 3.49-3.40 (m,2H), 3.36-3.20 (m, 2H), 2.19-2.08 (m, 2H) 92

20 440 ¹H NMR (500 MHz, DMSO-d₆) δ 9.20 (s, 1H), 8.89 (br s, 2H),8.43-8.35 (m, 2H), 8.23 (d, J = 8.5 Hz, 1H), 8.07 (d, J = 8.5 Hz, 1H),7.50 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 1.5, 1H), 7.13 (dd, J = 8.0, 2.0Hz, 1H), 4.53-4.48 (m, 2H), 3.80 (s, 3H), 3.51-3.45 (m, 2H), 3.19- 3.15(m, 2H), 2.12-2.08 (m, 2H) 93

26 469 ¹H NMR (500 MHz, DMSO-d₆) δ 8.88-8.81 (m, 2H), 8.16 (d, J = 8.5Hz, 1H), 7.83 (d, J = 7.5 Hz, 1H), 7.74 (d, J = 2.5 Hz, 1H), 7.67 (d, J= 7.5 Hz, 1H), 7.53 (dd, J = 8.0, 2.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H),7.18 (dd, J = 8.0, 2.5 Hz, 1H), 6.03 (d, J = 2.5 Hz, 1H), 5.21 (s, 2H),4.52-4.48 (m, 2H), 3.77 (s, 3H), 3.50-3.43 (m, 2H), 3.19-3.12 (m, 2H),2.13-2.05 (m, 2H) 94

11 437 ¹H NMR (500 MHz, DMSO-d₆) δ 8.86 (br s, 2H), 8.16 (d, J = 8.5 Hz,1H), 7.81 (d, J = 8.0 Hz, 1H), 7.67 (dd, J = 15.5, 8.5 Hz, 1H),7.40-7.34 (m, 2H), 7.18 (ddd, J = 8.5, 8.5, 2.5 Hz, 1H), 7.15 (dd, J =8.0, 3.0 Hz, 1H), 6.06 (d, J = 2.5 Hz, 1H), 5.17 (s, 2H), 4.51-4.45 (m,2H), 3.77 (s, 3H), 3.60-3.42 (m, 2H), 3.17-3.13 (m, 2H), 2.12-2.05 (m,2H) 95

7.8 439 ¹H NMR (500 MHz, DMSO-d₆) δ 8.91 (br s, 2H), 8.22 (d, J = 8.0Hz, 1H), 8.05-8.00 (m, 3H), 7.89 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.0,1H), 6.90 (s, 1H), 6.79 (d, J = 8.5 Hz, 1H), 4.53-4.47 (m, 2H), 3.79 (s,3H), 3.52-3.25 (m, 2H), 3.20- 3.13 (m, 2H), 2.13-2.07 (m, 2H) 96

9.2 453 ¹H NMR (500 MHz, DMSO-d₆) δ 8.92 (br s, 2H), 8.16 (d, J = 8.0Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.64 (dd, J = 8.0, 8.0 Hz, 1H), 7.55(dd, J = 10.0, 2.0 Hz, 1H), 7.41-7.35 (m, 2H), 6.15 (dd, J = 8.0, 2.5Hz, 1H), 6.05 (d, J = Hz, 1H), 5.19 (s, 2H), 4.52-4.45 (m, 2H), 3.76 (s,3H), 3.60-3.31 (m, 2H), 3.17-3.11 (m, 2H), 2.13-2.04 (m, 2H) 97

13 421 ¹H NMR (500 MHz, DMSO-d₆) δ 11.96 (s, 1H), 9.40-9.23 (m, 2H),7.50 (d, J = 8.3 Hz, 1H), 7.38-7.35 (m, 3H), 7.20 (t, J = 8.6 Hz, 2H),6.97 (d, J = 8.2 Hz, 1H), 4.23-3.79 (br m, 5H), 3.79- 3.42 (br m, 8H),3.40-3.34 (m, 2H), 3.29-3.22 (m, 2H), 3.19-3.04 (m, 4H) 98

13 435 ¹H NMR (500 MHz, DMSO-d₆) δ 11.46 (s, 1H), 10.50 (s, 1H), 7.51(d, J = 8.0 Hz, 1H), 7.40-7.33 (m, 3H), 7.25-7.14 (m, 2H), 6.96 (d, J =8.4 Hz, 1H), 4.21-3.79 (m, 5H), 3.75-3.39 (m, 7H), 3.38-3.17 (m, 6H),3.17-3.01 (m, 3H), 2.94 (d, J = 4.9 Hz, 3H) 99

17 449 ¹H NMR (500 MHz, DMSO-d₆) δ 11.44 (s, 1H), 10.16 (s, 1H), 7.51(d, J = 7.5 Hz, 1H), 7.41-7.38 (m, 3H), 7.23-7.15 (m, 2H), 6.97 (d, J =8.2 Hz, 1H), 4.23-3.79 (m, 5H), 3.71-3.43 (m, 6H), 3.38-3.17 (m, 9H),3.17-3.01 (m, 3H), 1.31 (t, J = 7.2 Hz, 3H) 100

10 434 ¹H NMR (500 MHz, CD₃OD) δ 7.58 (d, J = 8.5 Hz, 1H), 7.57 (d, J =7.5 Hz, 1H), 7.47 (d, J = 8.5 Hz, 2H), 7.43 (d, J = 8.5 Hz, 2H), 7.39(d, J = 1.5 Hz, 1H), 7.01 (dd, J = 8.5, 2.0 Hz, 1H), 6.28 (dd, J = 8.0,3.0 Hz, 1H), 6.11 (d, J = 2.5 Hz, 1H), 5.17 (s, 2H), 3.74 (s, 3H), 3.54(t, J = 5.5 Hz, 2H), 3.48 (t, J = 5.5 Hz, 2H), 3.35-3.33 (m, 2H), 3.23(t, J = 5.5 Hz, 2H) 101

9.9 399 ¹H NMR (500 MHz, CD₃OD) δ 8.03 (d, J = 7.0 Hz, 1H), 7.58 (d, J =8.5 Hz, 1H), 7.45 (d, J = 2.0 Hz, 1H), 7.30-7.28 (m, 4H), 7.22-7.17 (m,1H), 7.05 (dd, J = 8.5, 2.0 Hz, 1H), 6.56 (d, J = 6.5 Hz, 1H), 3.73 (s,3H), 3.42- 3.34 (m, 4H), 3.27-3.25 (m, 2H), 3.17- 3.15 (m, 2H),3.10-3.08 (m, 2H), 3.04-3.02 (m, 2H) 102

22 437 ¹H NMR (500 MHz, DMSO-d₆) δ 9.24 (s, 2H), 8.60 (d, J = 2.3 Hz,8.08-8.06 (m, 1H), 7.56-7.53 (m, 2H), 7.43 (d, J = 1.7 Hz, 1H), 6.95-6.94 (dd, J = 8.4, 1.8 Hz, 1H), 6.09- 6.05 (m, 2H), 5.27 (d, J = 1.6 Hz,2H), 3.69 (s, 3H), 3.37-3.35 (m, 2H), 3.35- 3.32 (m, 2H), 3.26-3.24 (m,2H), 3.13-3.11 (m, 2H) 103

6 418 ¹H NMR (500 MHz, CD₃OD) δ 7.63 (d, J = 8.5 Hz, 1H), 7.57 (d, J =7.5 Hz, 1H), 7.51 (dd, J = 8.5, 5.5 Hz, 2H), 7.44 (s, 1H), 7.15 (t, J =8.5 Hz, 2H), 7.06 (dd, J = 8.5, 2.0 Hz, 1H), 6.28 (dd, J = 7.5, 3.0 Hz,1H), 6.12 (d, J = 3.0 Hz, 1H), 5.16 (s, 2H), 4.55 (s, 2H), 3.77 (s, 3H),3.58 (t, J = 5.5 Hz, 2H), 3.20 (t, J = 5.5 Hz, 2H), 2.23- 2.19 (m, 2H)104

149 433 ¹H NMR (300 MHz, DMSO-d₆) δ 8.53 (d, J = 8.6 Hz, 1H), 8.48 (s,1H), 7.51-7.46 (m, 2H), 7.37-7.31 (m, 2H), 7.13-7.17 (dd, J = 8.5, 1.8Hz, 1H), 6.12-6.03 (m, 2H), 5.93-5.86 (m, 1H), 5.17 (s, 2H), 3.66 (s,3H), 3.42-3.34 (m, 2H), 3.09 (t, J = 6.8 Hz, 2H), 2.28-2.19 (m, 2H) 105

7.6 434 ¹H NMR (500 MHz, CD₃OD) δ 7.64 (d, J = 8.0 Hz, 2H), 7.48-7.42(m, 5H), 7.07 (dd, J = 8.0, 2.0 Hz, 1H), 6.37 (dd, J = 7.5, 2.5 Hz, 1H),6.17 (d, J = 3.0 Hz, 1H), 5.20 (s, 2H), 4.55 (s, 2H), 3.77 (s, 3H),3.59-3.57 (m, 2H), 3.22-3.19 (m, 2H), 2.26-2.18 (m, 2H) 106

18 437 ¹H NMR (500 MHz, DMSO-d₆) δ 8.99 (s, 2H), 8.60 (d, J = 2.3 Hz,1H), 8.10- 8.06 (dt, J = 10.2, 2.6 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H),7.56 (d, J = 7.3 Hz, 1H), 7.49 (d, J = 1.7 Hz, 1H), 7.01- 6.99 (dd, J =10.0, 2.6 Hz, 1H), 6.09-6.06 (m, 2H), 5.26 (s, 2H), 4.42-4.40 (m, 2H),3.71 (s, 3H), 3.44-3.41 (m, 2H), 3.10-3.08 (m, 2H), 2.09-2.03 (m, 2H)107

9.7 399 ¹H NMR (500 MHz, CD₃OD) δ 8.17 (d, J = 6.5 Hz, 1H), 7.67 (d, J =8.0 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H), 7.32-7.26 (m, 4H), 7.22-7.18 (m,1H), 7.15 (dd, J = 8.5, 2.0 Hz, 1H), 6.64 (d, J = 6.5 Hz, 1H), 4.56 (s,2H), 3.79 (s, 3H), 3.60-3.57 (m, 2H), 3.27-3.20 (m, 2H), 3.14-3.06 (m,4H), 2.23-2.18 (m, 2H) 108

60 440 ¹H NMR (500 MHz, CD₃OD) δ 9.47 (d, J = 1.5 Hz, 1H), 8.80 (dd, J =6.0, 2.0 Hz, 1H), 8.41 (d, J =6.5 Hz, 1H), 8.03 (d, J = 8.0 Hz, 1H),7.71 (d, J = 8.5 Hz, 1H), 6.64 (d, J = 1.5 Hz, 1H), 7.37 (d, J = 7.0 Hz,1H), 7.23 (dd, J = 8.5, 2.0 Hz, 1H), 4.58 (s, 2H), 3.72 (s, 3H),3.61-3.58 (m, 2H), 3.24-3.21 (m, 2H), 2.27-2.20 (m, 2H) 109

9.6 435 ¹H NMR (500 MHz, DMSO-d₆) δ 9.05 (s, 2H), 8.03 (d, J = 8.2 Hz,1H), 7.80 (d, J = 7.7 Hz, 1H), 7.50 (s, 4H), 7.31 (d, J = 8.2 Hz, 1H)6.17-6.15 (dd, J = 7.2, 2.7 Hz, 1H), 5.97 (d, J = 2.7 Hz, 1H), 5.17 (s,2H), 3.73 (s, 3H), 3.43- 3.37 (m, 2H), 3.37-3.31 (m, 2H), 3.30-3.25 (m,2H), 3.16-3.11 (m, 2H) 110

12 419 ¹H NMR (500 MHz, DMSO-d₆) δ 9.03 (s, 2H), 8.06 (d, J = 8.2 Hz,1H), 7.81 (d, J = 7.7 Hz, 1H), 7.54-7.41 (m, 2H), 7.30 (d, J = 8.2 Hz,1H), 7.29- 7.23 (m, 2H), 6.16-6.14 (dd, J = 7.2, 2.7 Hz, 1H), 5.99 (d, J= 2.6 Hz, 1H), 5.14 (s, 2H), 3.73 (s, 3H), 3.43-3.38 (m, 2H), 3.37-3.31(m, 2H), 3.30-3.26 (m, 2H), 3.16-3.11 (m, 2H) 111

71 438 ¹H NMR (500 MHz, DMSO-d₆) δ 9.08 (s, 2H), 8.59 (d, J = 2.3 Hz,1H), 8.09- 8.06 (dt, J = 9.5, 2.4 Hz, 1H), 8.02 (d, J = 8.2 Hz, 1H),7.77 (d, J = 7.7 Hz, 1H), 7.32 (d, J = 8.2 Hz, 1H), 6.15-6.12 (dd, J =7.7, 2.7 Hz, 1H), 6.07 (d, J = 2.7 Hz, 1H), 5.28 (s, 2H), 3.73 (s, 3H),3.42-3.37 (m, 2H), 3.36-3.31 (m, 2H), 3.30-3.26 (m, 2H), 3.16-3.11 (m,2H) 112

8.9 419 ¹H NMR (500 MHz, DMSO-d₆) δ 8.84 (s, 2H), 8.15 (d, J = 8.3 Hz,1H), 7.81 (d, J = 7.6 Hz, 1H), 7.55-7.51 (m, 2H), 7.37 (d, J =8.0 Hz,1H), 7.26 (t, J = 9.1 Hz, 2H), 6.17-6.14 (dd, J = 7.7, 2.6 Hz, 1H), 5.99(d, J = 2.7 Hz, 1H), 5.15 (s, 2H), 4.62-4.50 (m, 2H), 3.76 (s, 3H),3.49-3.44 (m, 2H), 3.16- 3.11 (m, 2H), 2.10-2.04 (m, 2H) 113

5.9 435 ¹H NMR (500 MHz, DMSO-d₆) δ 8.91 (s, 2H), 8.16 (d, J = 8.2 Hz,1H), 7.82 (d, J = 7.6 Hz, 1H), 7.50 (s, 4H), 7.37 (d, J = 8.2 Hz, 1H),6.18-6.16 (dd, J = 7.7, 2.6 Hz, 1H), 5.97 (d, J = 2.7 Hz, 1H), 5.17 (s,2H), 4.49-4.45 (m, 2H), 3.76 (s, 3H), 3.49-3.42 (m, 2H), 3.16- 3.11 (m,2H), 2.10-2.04 (m, 2H) 114

44 438 ¹H NMR (500 MHz, DMSO-d₆) δ 8.92 (s, 2H), 8.59 (d, J = 2.3 Hz,1H), 8.17 (d, J = 8.3 Hz, 1H), 8.09-8.05 (dt, J = 9.5, 2.3 Hz, 1H), 7.81(d, J = 7.7 Hz, 1H), 7.36 (d, J = 8.2 Hz, 1H), 6.15-6.12 (dd, J = 7.7,2.7 Hz, 1H), 6.08 (d, J = 2.7 Hz, 1H), 5.28 (s, 2H), 4.49-4.45 (m, 2H),3.73 (s, 3H), 3.48-3.43 (m, 2H), 3.15-3.11 (m, 2H), 2.11-2.05 (m, 2H)

As compounds that bind strongly to MCH-1, compounds of formula I areexpected to be effective in reducing obesity.

The present invention is not limited to the compounds found in the aboveexamples, and many other compounds falling within the scope of theinvention may also be prepared using the procedures set forth in theabove synthetic schemes. The preparation of additional compounds offormula (I) using these methods will be apparent to one of ordinaryskill in the chemical arts.

Although preferred embodiments have been depicted and described indetail herein, it will be apparent to those skilled in the relevant artthat various modifications, additions, substitutions, and the like canbe made without departing from the spirit of the invention and these aretherefore considered to be within the scope of the invention as definedin the claims which follow.

1. A compound of formula (I):

wherein R¹ is selected from the group consisting of H, —S(O)₁R¹⁴,C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, and heteroaryl, whereineach of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,C₄-C₇ cycloalkylalkyl, heterocyclyl, and heteroaryl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹⁶, NR¹⁶R¹⁷, andphenyl which is optionally substituted 1-3 times with halogen, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹⁶, or —NR¹⁶R¹⁷; R²-R⁵ andR⁹-R¹² are each, independently, selected from the group consisting of H,halogen, —OR¹³, —NR¹³R¹⁴, —NR¹³C(O)R¹⁴, —NR¹³C(O)₂R¹⁴, —NR¹⁵C(O)NR¹⁴R¹⁵,—S(O)_(q)R¹⁴, —CN, —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl,aryl, and heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl,and heteroaryl is optionally substituted with from 1 to 3 substituentsindependently selected at each occurrence thereof from C₁-C₃ alkyl,halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, and phenyl which is optionallysubstituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, —CN, —OR¹⁶, or —NR¹⁶R¹⁷; or R² and R³ or R⁴ and R⁵ can combineto form an oxo, thio, imine, cycloalkyl, or heterocycle group containingfrom 1 to 5 heteroatoms selected from the group consisting of oxygen,nitrogen, and sulfur; R⁶ is independently selected at each location fromthe group consisting of H, halogen, —OR¹³, —NR¹³R¹⁴, —NR¹³C(O)R¹⁴,—NR¹³C(O)₂R¹⁴, —NR¹⁵C(O)NR¹⁴R¹⁵, —S(O)_(q)R¹⁴, —CN, —C(O)R¹⁴,—C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂C-₂ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl,wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl isoptionally substituted with from 1 to 3 substituents independentlyselected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN,—OR¹⁶, —NR¹⁶R¹⁷, and phenyl which is optionally substituted 1-3 timeswith halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹⁶, or—NR¹⁶R¹⁷; R⁷ is optionally present and, if present, is selected from thegroup consisting of H, halogen, —OR¹³, —NR¹³R₁₄, —NR¹³C(O)NR¹⁴,—NR¹³C(O)₂R¹⁴, —NR¹⁵C(O)¹⁴R¹⁵, —S(O)_(q)R¹⁴, —CN, —C(O)R¹⁴,—C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl,wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl isoptionally substituted with from 1 to 3 substituents independentlyselected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN,—OR¹⁶, —NR¹⁶R¹⁷, and phenyl which is optionally substituted 1-3 timeswith halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹⁶, or—NR¹⁶R¹⁷; or R² and R³ or R⁴ and R⁵ can combine to form an oxo, thio,imine, cycloalkyl, or heterocycle group containing from 1 to 5heteroatoms selected from the group consisting of oxygen, nitrogen, andsulfur; R⁸ is selected from the group consisting of H, —S(O)_(q)R¹⁴,—C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, and heteroaryl, whereineach of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,C₄-C₇ cycloalkylalkyl, heterocyclyl, and heteroaryl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, andphenyl which is optionally substituted 1-3 times with halogen, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹⁶, or —NR¹⁶R¹⁷; R¹³ is H,C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —C(O)R¹⁵, phenyl, or benzyl, wherein phenyl or benzylis optionally substituted 1 to 3 times with halogen, cyano, C₁-C₄ alkyl,C₁-C₄ haloalkyl, or C₁-C₄ alkoxy; R¹⁴ is H, C₁-C₄ alkyl, C₁-C₄haloalkyl, C₁-C₄ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,phenyl, or benzyl, wherein phenyl or benzyl is optionally substituted 1to 3 times with halogen, cyano, C₁--C₄ alkyl, C₁--C₄ haloalkyl, or C₁-C₄alkoxy; R¹⁵ is C₁-C₄ alkyl, C₁-C₄ haloalkyl, or phenyl; R¹⁶ and R¹⁷ areeach independently H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxyalkyl,C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —C(O)R¹⁵, phenyl, or benzyl,wherein phenyl or benzyl is optionally substituted from 1 to 3 timeswith a substituent selected independently at each occurrence thereoffrom the group consisting of halogen, cyano, C₁-C₄ alkyl, C₁-C₄haloalkyl, and C₁-C₄ alkoxy; R¹⁸ is selected from the group consistingof H, halogen, —OR¹³, —NR¹³R¹⁴—NR¹³C(O)R¹⁴, —NR¹³C(O)₂R¹⁴,—NR¹⁴C(O)NR¹⁴R¹⁵, —S(O)_(q) ^(R) ¹⁴, —CN, —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆alkyl. C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,heterocyclyl, aryl, and heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1to 3 substituents independently selected at each occurrence thereof fromC₁-C₃ alkyl, halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, and phenyl which isoptionally substituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄haloalkyl, C₁-C₄ alkoxy, —CN, —OR⁸, or —NR⁸R⁹; G is—NR⁸—CR⁹R¹⁰—CR¹¹R¹²—, —CR⁹R¹⁰—NR⁸—CR¹¹R¹²—, or —CR⁹R¹⁰—CR¹¹R¹²—NR⁸—,with the proviso that when G is —CR⁹R¹⁰—NR⁸—CR¹¹R¹²—, R² and R³ are not—C(O)NR¹³R¹⁴; X is CR¹⁸, C(R¹⁸)₂, N, or NR¹⁸; Y is CR¹⁸, C, or N; Z isCH, C, or N; L is —(CH₂)_(p)—O—, —(CH₂)_(p)—, —CH═CH—, or a bond; A isCH, C, or N; B is aryl, heteroaryl, heterocyclyl, or cycloalkyl, whereineach of the aryl, heteroaryl, heterocyclyl, or cycloalkyl is optionallysubstituted with from 1 to 3 substituents selected from the groupconsisting of H, alkoxy, —S-alkyl, optionally substituted C₁-C₆ alkyl,halogen, —CF₃, and —CN; n is 0, 1, 2, or 3; p is from 1 to 4; q is 0, 1,or 2; and

represents an optional double bond, or an oxide thereof, apharmaceutically acceptable salt thereof, a solvate thereof, or prodrugthereof.
 2. The compound according to claim 1, wherein G is—NR⁸—CR⁹R¹⁰—CR¹¹R¹²—.
 3. The compound according to claim 2, wherein R⁸is H or C₁-C₆ alkyl and R⁹—R¹² are H.
 4. The compound according to claim1, wherein G is —CR⁹R¹⁰—NR⁸—CR¹¹R¹²—.
 5. The compound according to claim4, wherein R⁸ is H or C₁-C₆ alkyl and R⁹—R¹² are H.
 6. The compoundaccording to claim 1, wherein G is —CR⁹R¹⁰—CR¹¹R¹²—NR⁸—.
 7. The compoundaccording to claim 6, wherein R⁸ is H or C₁-C₆ alkyl and R⁹—R¹² are H.8. The compound according to claim 1, wherein R¹ is H.
 9. The compoundaccording to claim 1, wherein R¹ is C₁-C₆ alkyl.
 10. The compoundaccording to claim 1, wherein R¹ is selected from the group consistingof H, —S(O)_(q)R¹⁴, —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl,and C₂-C₆ alkynyl.
 11. The compound according to claim 1, wherein R⁸ isH or C₁-C₆ alkyl.
 12. The compound according to claim 1, wherein R⁴ andR⁵ are combined to form an oxo group.
 13. The compound according toclaim 1, wherein X is N, CH, or CH₂.
 14. The compound according to claim1, wherein Y is N, C, or CH.
 15. The compound according to claim 1,wherein L is a bond.
 16. The compound according to claim 1, wherein L is—CH₂—O—.
 17. The compound according to claim 1, wherein L is —CH₂—CH₂—.18. The compound according to claim 1, wherein B phenyl, pyridinyl,pyridazinyl, or pyrimidinyl.
 19. The compound according to claim 1,wherein B is unsubstituted.
 20. The compound according to claim 1,wherein B is substituted with at least one substituent selected fromtrifluoromethyl, chloro, fluoro, methyl, and methanethio.
 21. Thecompound according to claim 1, wherein B is selected from the groupconsisting of phenyl, 4-(trifluoromethyl)phenyl, 4-(methylthio)-phenyl,5-(trifluoromethyl)pyridin-2-yl, 2-(trifuloromethyl)-pyrimidin-5-yl,6-(trifluoromethyl)pyridazin-3-yl, 5-fluoro-pyridin-2-yl,6-methylpyridin-3-yl, 6-(trifluoromethyl)pyridin-3-yl,5-chloro-pyridin-2-yl, 2,4-dichloro-phenyl, 2,4-difluoro-phenyl,4-chloro-phenyl, 4-chloro-2-fluoro-phenyl, 3,5-dichloro-pyridin-2-yl,4-fluoro-phenyl, pyridin-2-yl, and 3,5-difluoro-pyridin-2-yl.
 22. Thecompound according to claim 1, wherein the compound has the structure:


23. The compound according to claim 1, wherein the compound is selectedfrom the group consisting of


24. The compound according to claim 1, wherein the compound is selectedfrom the group consisting of


25. The compound according to claim 1, wherein the compound is selectedfrom the group consisting of


26. The compound according to claim 1, wherein the compound is an HClsalt.
 27. A pharmaceutical composition comprising a therapeuticallyeffective amount of the compound according to claim 1 and apharmaceutically acceptable carrier.
 28. A method of treating a diseaseor condition which is susceptible to treatment with a MCH-1 receptorantagonist comprising: selecting a patient with a disease or conditionwhich is susceptible to treatment with a MCH-1 antagonist, andadministering to the patient a therapeutically effective amount of acompound of claim 1 or a pharmaceutically acceptable salt thereof 29.The method according to claim 28, wherein the disease or condition isselected from the group consisting of obesity, general anxietydisorders, social phobias, vertigo, obsessive-compulsive disorders,panic disorders, post-traumatic stress disorders, Parkinson's DiseasePsychosis, schizophrenia, cognitive decline and defects inschizophrenia, presenile dementias, Alzheimer's Disease, psychologicaldisorders, depression, substance abuse disorders, dementia associatedwith neurodegenerative disease, cognition deficits, and epilepsy. 30.The method according to claim 29 further comprising: administering tothe patient a therapeutically effective amount of a therapeutic adjunct.31. The method according to claim 30, wherein the therapeutic adjunct isselected from the group consisting of phenylpropanolamine, ephedrine,pseudoephedrine, phentermine, a cholecystokinin-A agonist, a monoaminereuptake inhibitor, a sympathomimetic agent, a serotonergic agent, adopamine agonist, a melanocyte-stimulating hormone receptor agonist ormimetic, a melanocyte-stimulating hormone analog, a cannabinoid receptorantagonist or inverse agonist, a melanin concentrating hormone receptorantagonist, a serotonin 5-HT₆ receptor antagonist, a serotonin 5-HT_(2C)receptor agonist, leptin, a leptin analog, a leptin receptor agonist,amylin peptide, an amylin analog, an amylin receptor agonist, aneuropeptide Y receptor modulator, a galanin antagonist, a GI lipaseinhibitor or decreaser, a bombesin agonist, dehydroepiandrosterone oranalogs thereof, a glucocorticoid receptor agonist, a glucocorticoidreceptor antagonist, an orexin receptor antagonist, an urocortin bindingprotein antagonist, an agonist of the glucagon-like peptide-1 receptor,a ciliary neurotrophic factor, an allosteric modulator of the GABA_(A)receptor, a serotonin 5-HT_(1A) receptor partial agonist, a selectiveserotonin reuptake inhibitor, a serotonin-norepinephrine reuptakeinhibitor, a monoamine neurotransmitter reuptake inhibitor of tricyclicantidepressant class, a combined serotonin reuptake inhibitor and5-HT_(2C) antagonist, an H₁ receptor antagonist, a noradrenergic andspecific serotonergic antidepressant, a norepinephrine reuptakeinhibitor, a norepinephrine-dopamine reuptake inhibitor, a monoamineoxidase inhibitor, an AMP-activated protein kinase agonist, a peroxisomeproliferator-activated receptor gamma activator, a HMG-CoA reductaseinhibitor, a PDE4 inhibitor, and combinations thereof.
 32. A method oftreating obesity in a subject in need of weight loss comprising:selecting a patient in need of weight loss, and administering to thepatient a therapeutically effective amount of a compound of claim 1 or apharmaceutically acceptable salt thereof
 33. The method according toclaim 32 further comprising: administering to the patient atherapeutically effective amount of an anti-obesity adjunct.
 34. Themethod according to claim 33, wherein the anti-obesity adjunct isselected from the group consisting of phenylpropanolamine, ephedrine,pseudoephedrine, phentermine, a cholecystokinin-A agonist, a monoaminereuptake inhibitor, a sympathomimetic agent, a serotonergic agent, adopamine agonist, a melanocyte-stimulating hormone receptor agonist ormimetic, a melanocyte-stimulating hormone analog, a cannabinoid receptorantagonist or inverse agonist, a melanin concentrating hormone receptorantagonist, a serotonin 5-HT₆ receptor antagonist, a serotonin 5-HT_(2C)receptor agonist, leptin, a leptin analog, a leptin receptor agonist,amylin peptide, an amylin analog, an amylin receptor agonist, aneuropeptide Y receptor modulator, a galanin antagonist, a GI lipaseinhibitor or decreaser, a bombesin agonist, dehydroepiandrosterone oranalogs thereof, a glucocorticoid receptor agonist, a glucocorticoidreceptor antagonist, an orexin receptor antagonist, an urocortin bindingprotein antagonist, an agonist of the glucagon-like peptide-1 receptor,a ciliary neurotrophic factor, and combinations thereof.
 35. A method oftreating obesity in a subject who has experienced weight losscomprising: selecting a patient who has experienced weight loss, andadministering to the patient a therapeutically effective amount of acompound of claim 1 or a pharmaceutically acceptable salt thereof
 36. Amethod of treating anxiety comprising: selecting a patient with anxiety,and administering to the patient a therapeutically effective amount of acompound of claim 1 or a pharmaceutically acceptable salt thereof 37.The method according to claim 36 further comprising: administering tothe patient a therapeutically effective amount of a anti-anxietyadjunct.
 38. The method according to claim 37, wherein the anti-anxietyadjunct is selected from the group consisting of an allosteric modulatorof the GABA_(A) receptor, a serotonin 5-HT_(1A) receptor partialagonist, a selective serotonin reuptake inhibitor, aserotonin-norepinephrine reuptake inhibitor, a monoamineneurotransmitter reuptake inhibitor of tricyclic antidepressant class, acombined serotonin reuptake inhibitor and 5-HT_(2C) antagonist, an H₁receptor antagonist, and combinations thereof.
 39. A method of treatingdepression comprising: selecting a patient with depression, andadministering to the patient a therapeutically effective amount of acompound of claim 1 or a pharmaceutically acceptable salt thereof 40.The method according to claim 39 further comprising: administering tothe patient a therapeutically effective amount of an anti-depressionadjunct.
 41. The method according to claim 40, wherein theanti-depression adjunct is selected from the group consisting of aserotonin 5-HT_(1A) receptor partial agonist, a selective serotoninreuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, amonoamine neurotransmitter reuptake inhibitor of tricyclicantidepressant class, a combined serotonin reuptake inhibitor and5-HT_(2C) antagonist, a noradrenergic and specific serotonergicantidepressant, a norepinephrine reuptake inhibitor, anorepinephrine-dopamine reuptake inhibitor, a monoamine oxidaseinhibitor, and combinations thereof.
 42. A method of treatingnon-alcoholic fatty liver disease comprising: selecting a patient whohas non-alcoholic fatty liver disease, and administering to the patienta therapeutically effective amount of a compound of claim 1 or apharmaceutically acceptable salt thereof
 43. The method according toclaim 42 further comprising: administering to the patient atherapeutically effective amount of an anti-non-alcoholic fatty liverdisease adjunct.
 44. The method according to claim 43, wherein theanti-non-alcoholic fatty liver disease adjunct is selected from thegroup consisting of an AMP-activated protein kinase agonist, aperoxisome proliferator-activated receptor gamma activator, a HMG-CoAreductase inhibitor, a PDE4 inhibitor, and combinations thereof.
 45. Aprocess for the preparation of a product compound of formula (I):

wherein R¹ is selected from the group consisting of H, —S(O)_(q)R¹⁴,—C(O)R¹⁴,—C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, and heteroaryl, whereineach of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,C₄-C₇ cycloalkylalkyl, heterocyclyl, and heteroaryl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, andphenyl which is optionally substituted 1-3 times with halogen, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹⁶, or —NR¹⁶R¹⁷; R²—R⁵ andR⁹—R¹² are each, independently, selected from the group consisting of H,halogen, —OR¹³, —NR¹³R¹⁴, —NR¹³C(O)R¹⁴, —NR¹³C(O)₂R¹⁴, —NR¹⁵C(O)NR¹⁴R¹⁵,—S(O)_(q)R¹⁴, —CN, —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl,aryl, and heteroaryl, wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl,and heteroaryl is optionally substituted with from 1 to 3 substituentsindependently selected at each occurrence thereof from C₁-C₃ alkyl,halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, and phenyl which is optionallysubstituted 1-3 times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄alkoxy, —CN, —OR¹⁶, or —NR¹⁶R¹⁷; or R² and R³ or R⁴ and R⁵ can combineto form an oxo, thio, imine, cycloalkyl, or heterocycle group containingfrom 1 to 5 heteroatoms selected from the group consisting of oxygen,nitrogen, and sulfur; R⁶ is independently selected at each location fromthe group consisting of H, halogen, —OR¹³, —NR¹³C(O)R¹⁴,—NR^(—)C(O)₂R¹⁴, —NR¹⁵C(O)NR¹⁴R¹⁵, —S(O)_(q)R¹⁴, —CN, —C(O)R¹⁴,C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl,wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl isoptionally substituted with from 1 to 3 substituents independentlyselected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN,—OR¹⁶, —NR¹⁶, —NR¹⁶R¹⁷, and phenyl which is optionally substituted 1-3times with halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN,—OR¹⁶, or —NR¹⁶R¹⁷; R⁷ is optionally present and, if present, isselected from the group consisting of H, halogen, —OR¹³, —NR¹³R¹⁴,—NR¹³C(O)R¹⁴, —NR¹³C(O)₂R¹⁴, NR¹⁵C(O)NR¹⁴R¹⁵, —S(O)_(q)R¹⁴, —CN,—C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl,wherein each of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl isoptionally substituted with from 1 to 3 substituents independentlyselected at each occurrence thereof from C₁-C₃ alkyl, halogen, —CN,—OR¹⁶, —NR¹⁶R¹⁷, and phenyl which is optionally substituted 1-3 timeswith halogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN,—OR¹⁶, or—NR¹⁶R¹⁷; or R² and R³ or R⁴ and R⁵ can combine to form an oxo, thio,imine, cycloalkyl, or heterocycle group containing from 1 to 5heteroatoms selected from the group consisting of oxygen, nitrogen, andsulfur; R⁸ is selected from the group consisting of H, —S(O)_(q)R¹⁴,—C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆cycloalkyl, C₄-C₇ cycloalkylalkyl, heterocyclyl, and heteroaryl, whereineach of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl,C₄-C₇ cycloalkylalkyl, heterocyclyl, and heteroaryl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, andphenyl which is optionally substituted 1-3 times with halogen, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR¹⁶, or —NR¹⁶R¹⁷; R¹³ is H,C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, —C(O)R¹⁵, phenyl, or benzyl, wherein phenyl or benzylis optionally substituted 1 to 3 times with halogen, cyano, C₁-C₄ alkyl,C₁-C₄ haloalkyl, or C₁-C₄ alkoxy; R¹⁴ is H, C₁-C₄ alkyl, C₁-C₄haloalkyl, C₁-C₄ alkoxyalkyl, C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl,phenyl, or benzyl, wherein phenyl or benzyl is optionally substituted 1to 3 times with halogen, cyano, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄alkoxy; R¹⁵ is C₁-C₄ alkyl, C₁-C₄ haloalkyl, or phenyl; R¹⁶ and R¹⁷ areeach independently H, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxyalkyl,C₃-C₆ cycloalkyl, C₄-C₇ cycloalkylalkyl, —C(O)R¹⁵, phenyl, or benzyl,wherein phenyl or benzyl is optionally substituted from 1 to 3 timeswith a substituent selected independently at each occurrence thereoffrom the group consisting of halogen, cyano, C₁-C₄ alkyl, C₁-C₄haloalkyl, and C₁-C₄ alkoxy; R¹⁸ is selected from the group consistingof H, halogen, —OR¹³, —NR¹³R¹⁴—NR¹³C(O)R¹⁴, —NR¹³C(O)₂R¹⁴,—NR¹⁴C(O)NR¹⁴R¹⁵, —S(O)_(q)R¹⁴, —CN, —C(O)R¹⁴, —C(O)NR¹³R¹⁴, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each ofC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₄-C₇cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionallysubstituted with from 1 to 3 substituents independently selected at eachoccurrence thereof from C₁-C₃ alkyl, halogen, —CN, —OR¹⁶, —NR¹⁶R¹⁷, andphenyl which is optionally substituted 1-3 times with halogen, C₁-C₄alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, —CN, —OR⁸, or —NR⁸R⁹; G is—NR⁸—CR⁹R¹⁰—CR¹¹R¹²—, —CR⁹R¹⁰—NR⁸—CR¹¹R¹²—, or —CR⁹R¹⁰—CR¹¹R¹²—NR⁸—,with the proviso that when G is —CR⁹R¹⁰—NR⁸—CR¹¹R¹²—, R² and R³ are not—C(O)NR¹³R¹⁴; X is CR¹⁸, C(R¹⁸)₂, N, or NR¹⁸; Y is CR¹⁸, C, or N; Z isC, CH, or N; L is —(CH₂)_(p)—O—, —(CH₂)_(p)—, —CH═CH—, or a bond; A isC, CH, or N; B is aryl, heteroaryl, heterocyclyl, or cycloalkyl, whereineach of the aryl, heteroaryl, heterocyclyl, or cycloalkyl is optionallysubstituted with from 1 to 3 substituents selected from the groupconsisting of H, alkoxy, -S-alkyl, optionally substituted C₁-C₆ alkyl,halogen, —CF₃, and —CN; n is 0, 1, 2, or 3; p is from 1 to 4; q is 0, 1,or 2; and

represents an optional double bond, said process comprising: treating afirst intermediate of formula (II):

wherein Q is a halogen, under conditions effective to form the compoundof formula (I).